Bioactive Natural Products: Opportunities and Challenges in

b1214 Bioactive Natural Products

Natural Products in DrugDiscovery: Impacts andOpportunities — An Assessment

Goutam Brahmachari*

Nature stands as an inexhaustible source of novel chemotypes and phar-

macophores, and has been a source of medicinal agents for thousands of

years, and an impressive number of modern drugs find their origin in

natural products. Natural product chemistry has experienced explosive

and diversified growth, making natural products the subject of much

interest and promise in the present day research directed towards drug

design and discovery. It is noteworthy that natural products are a source

of new compounds with diversified structural arrangements possessing

interesting biological activities. Natural products, thus, have played and

continue to play an invaluable role in the drug discovery process.

Recently, there has been a renewed interest in natural products research

due to the failure of alternative drug discovery methods to deliver many

lead compounds in key therapeutic areas such as immunosuppression,

anti-infective, and metabolic diseases. However, continuing improve-

ments in natural products research are needed to continue to be

competitive with other drug discovery methods, and also to keep pace

with the ongoing changes in the drug discovery process. Faithful drives

are needed in a more intensified fashion to explore “Nature” as a source

of novel and active agents that may serve as the leads and scaffolds for

elaboration into urgently needed efficacious drugs for a multitude of dis-

ease indications.

Natural products have provided considerable value to the pharma-

ceutical industry over the past half century. In particular, the therapeutic

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* Corresponding author. E-mail: [email protected]; [email protected]

b1214_Chapter-01.qxd 9/7/2011 4:23 PM Page 1

areas of infectious diseases and oncology have benefited much from

numerous drug classes derived from the natural form and as templates

for synthetic modification. About 40 new drugs launched on the market

between 2000 and 2010, originating from terrestrial plants, terrestrial

microorganisms, marine organisms, and terrestrial vertebrates and inver-

tebrates are reported, and summarized categorically (as per disease area)

in this article. In addition, this review incorporates natural products and

natural product-derived compounds that are being presently evaluated in

clinical trials or are in registration highlighting their mechanism of

action. These drugs substances, representative of very wide chemical

diversity, thus continue to demonstrate the importance of compounds

from natural sources in modern drug discovery efforts. Hence, the

proven natural product drug discovery track record, coupled with the

continuing threat to biodiversity through the destruction of terrestrial

and marine ecosystems, provides a compelling challenge for the global

scientific community to undertake expanded exploration of “Nature” as

a source of novel leads for the development of drugs and other valuable

bioactive agents. A huge number of natural product-derived compounds

in various stages of clinical development highlight the existing viability

and significance of the use of natural products as sources of new drug

candidates.

“Organic chemistry just now is enough to drive one mad. It gives the

impression of a primeval tropic forest, full of the most remarkable

things, a monstrous and boundless thicket, with no way to escape, into

which one may well dread to enter.”

Wöhler (1835)

1. Introduction

Almost two centuries had elapsed after Wöhler’s historical comment citedin his letter to Berzelius in the year 1835 on the ongoing development oforganic chemistry; his “monstrous and boundless thicket” is now suffi-ciently more dense and complex than ever and quite forbidding tostrangers! Natural products chemistry, a vital section of organic chemistry,

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has also undergone an explosive growth in its own course and has alreadyestablished itself as a distinct discipline. Mother Nature now stands as aninexhaustible source of novel chemotypes and pharmacophores.1

Nature’s terrestrial flora and fauna have formed the basis of sophisti-cated traditional medicine systems that have been in existence forthousands of years — such an intrinsic dependence of human beings onNature has invoked tremendous interest in the scientific world, which ulti-mately led to the isolation of a vast number of chemical agents with thepotential for multipurpose uses.2–9 Natural product chemists took up thechallenge of determining the structures of ever more complicated naturalproducts. From the late 19th century until today, generations of naturalproduct chemists have applied their skills and intellect to many tens ofthousands of molecules of natural origin, encouraged by a society that val-ues many natural products for their life-giving or life-enhancing properties.Although ~200 000 natural compounds derived from natural sources suchas plants, animals or microorganisms are currently known, this figure iswith small variety regards to the widen of natural resources; only about5–15% of nearly 250 000 higher plants and less than 1% of the microbialworld have been explored so far chemically — the vast majority of thesesources remains untapped.10–12 The future of natural products in drug dis-covery, thus, appears to be a tale of justifiable hope. The pragmaticoptimism currently placed on natural products in search of new drugs andlead molecules has recently been aptly expressed as “The world of plants,and indeed all natural sources, represent a virtually untapped reservoir ofnovel drugs awaiting imaginative and progressive organizations”.1

By the 20th century, natural products began to provoke some bio-chemists interested in understanding the way in which compounds weremade that eventually initiated the concepts of biosynthetic pathways for dif-ferent kinds of natural products. In the early 20th century, very fewresearchers associated with the emerging departments of clinical biochem-istry, pharmacology, toxicology, microbiology and cell biology becamemotivated to work with some specific natural products, but the study of nat-ural products as a group was still largely confined to chemistry departments.By the mid 20th century, some cell biologists and physiologists screened afew natural products (viz. colchicine, atropine, nicotine, digoxin, etc.) asexperimental tools that influenced or disrupted cell functions in specific

Natural Products in Drug Discovery 3



ways. However, it was the discovery of antibiotics that offered the study ofnatural products a great boost in microbiology departments and ensured thatnatural products remained central to growing pharmaceutical companies.13,14

Due to multidirectional promising aspects, the interest in naturalproducts continues to this very day.15–30 The last decade has seen a greateruse of botanical products among members of the general public throughself-medication than never before. The use of herbal drugs is once moreescalating in the form of complementary and alternative medicine(CAM).31,32 This phenomenon has been mirrored by an increasing atten-tion to phytomedicines as a form of alternative therapy by the healthprofessions; in many developing countries of the world, there is still amajor reliance on crude drug preparation of plants used in traditional med-icines for their primary healthcare.33–36 The World Health Organization(WHO) estimates that approximately 80% of the world’s population reliesmainly on traditional medicine, predominantly originated from plants, fortheir primary health care.37,38 The worldwide economic impact of herbalremedies is noteworthy; in the US alone, in 1997, it was estimated that12.1% of the population spent $5.1 billion on herbal remedies.39 In the UK,sales of herbal remedies were worth of £75 million in 2002, an increaseof 57% over the previous 5 years of herbal medicines.40 Studies carriedout in other countries, such as Australia and Italy, also suggest an increas-ing prevalence of use of herbal medicines among the adult population.40,41

In India and China, the Ayurvedic and Chinese traditional medicine sys-tems respectively are particularly well developed, and both have providedpotential for the development of Western medicine. Throughout our evo-lution, the importance of natural products for medicine and health hasbeen enormous; the past few years have seen a renewed interest in the useof natural compounds and, more importantly, their role as a basis for drugdiscovery. The modern tools of chemistry and biology — in particular, thevarious “-omics” technologies — now allow scientists to detail the exactnature of the biological effects of natural compounds on the human body,as well as to uncover possible synergies, which holds much promise forthe discovery of new therapies against many devastating diseases.42–49

Natural products, thus, have been the major sources of chemicaldiversity as starting materials for driving pharmaceutical discovery overthe past century.1,50,51 Many natural products and synthetically modified

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natural product derivatives have been successfully developed for clinicaluse to treat human diseases in almost all therapeutic areas.52 Natural prod-uct medicines have come from various source materials includingterrestrial plants, terrestrial microorganisms, marine organisms, and ter-restrial vertebrates and invertebrates.4,8,41,42 The importance of naturalproducts in modern medicine has been described in a number of earlierreviews and reports.8,30,53–60

A comprehensive review of natural products in clinical trials, “RecentNatural Products Based Drug Development: A Pharmaceutical IndustryPerspective”, was published in 1998 by Shu.61 Since then, a good numberof discussions have been published that describe natural product-derivedcompounds in clinical trials by organism type, compound class and/ortherapeutic area.48,53–71 In addition, there have been a number of reviewsdetailing marine-derived natural products in clinical trials.47,57,72–80 Thispresent chapter is aimed, particularly, to highlight the impact and oppor-tunities of natural products in modern drug discovery programsdelineating the approved natural product-based drugs launched during theperiod 2000 to 2010, and also natural product-based drug candidatesundergoing clinical evaluation.

2. Natural Products in Traditional Medicine:A Historical Perspective in Brief

Natural products (including plants, animals and minerals) have been thebasis of treatment of human diseases. History of medicine dates backpractically to the existence of human civilization. Modern medicine sys-tem has gradually developed over the years by scientific and observationalefforts of scientists; however, the basis of its development remains rootedin traditional medicine and therapies, prevailing throughout the world forthousands of years, which continue to provide mankind with new remedies.Plant-based medicines initially dispensed in the form of crude drugs suchas tinctures, teas, poultices, powders, and other herbal formulations,6 nowserve as the basis of novel drug discovery. The plant-based indigenousknowledge was passed down from generation to generation in variousparts of the world throughout its history and has significantly contributedto the development of different traditional systems of medicine.




The history of traditional medicine in India can be traced to theremote past. Multidirectional therapeutic uses of various plants in tradi-tional way are known in India since the Vedic times as Ayurvedic andUnani systems of medicine. The lore of any country man is built upon theexperience of generations, often of centuries and the data upon which it isbased have often been obtained at a price in human lives which no mod-ern research worker would ever dream of considering. The earliestmention of the medicinal use of plants is found in the Rig Veda, perhapsthe oldest repository of human knowledge, having been written between4500 and 1600 BC. “Susruta Samhita” which was written not later than1000 BC contains a comprehensive chapter on therapeutics and “CharakaSamhita”, written about the same period, gives a remarkable descriptionof the materia medica as it was known to the ancient Hindus. During thecenturies that have gone by, the materia medica of the indigenous systemof medicine has become explosive and heterogeneous.

The “Nei Ching” is also one of the earliest health science anthologies,which dates back to 1300 BC.81 Some of the first records on the use of nat-ural products in medicine were written in cuneiform in Mesopotamia onclay tablets and date to approximately 2600 BC.81,82 Indeed, many of theseagents continue to exist in one form or another to this day as treatments forvarious ailments. Chinese herb guides document the use of herbaceousplants as far back in times as 2000 BC;22 in fact, “The Chinese MeteriaMedica” has been repeatedly documented over centuries starting at about1100 BC.82 Li Shih-Chen produced a Chinese drug encyclopedia duringthe Ming Dynasty entitled “Pen-ts’as kang mu” in AD 1596, which records1898 herbal drugs and 8160 prescriptions.71 Egyptians have been found tohave documented uses of various herbs in 1500 BC;22,82 the best known ofthese documents is the Ebers Papyrus, which documents nearly 1000 dif-ferent substances and formulations, most of which are plant-basedmedicines.81 The Greek Botanist, Pedanius Dioscorides compiled a workentitled “De Materia Medica” in approximately AD 100, and this is still avery well-known European document on the use of herbs in medicine.However, it should not go unrecognized that it was the Arabs who wereresponsible for maintaining the documentation of much of the Greek andRoman knowledge of herbs and natural products and expanding that infor-mation with their own knowledge of Chinese and Indian herbal medicine.82

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Besides, various types of societies and botanical clubs held meetings andpublished different types of communications to educate the general peoplewith regard to the availability of natural products and how they could behelpful to an individual’s health. Samuel Thompson’s “Thompson’s NewGuide to Health” was also one very popular publication. For a variety ofreasons, the interest in natural products continues to this veryday.16,17,19,20–22,83,84

In many developing countries of the world, there is still a majorreliance on crude drug preparation of plants used in traditional medicinesfor their primary health care.33–36 Pharmacognosists employed in the dif-ferent institutions are aware of the changing trends of herbal medicationsand a number of useful texts on the analysis, uses, and potential toxicitiesof herbal remedies have appeared recently, which serves as useful guidesin pharmacy practice. The history of medicine includes many ludicroustherapies. Nevertheless, ancient wisdom has been the basis of modernmedicine and will remain as one important source of future medicine andtherapeutics. The future of natural products drug discovery will be moreholistic, personalized and involve the wise use of ancient and modern ther-apeutic skills in a complementary manner so that maximum benefits can beaccrued to the patients and the community.85

The use of natural products as medicine has invoked the isolation ofactive compounds; the first commercial pure natural product introducedfor therapeutic use is generally considered to be the narcotic morphine (1),marketed by Merck in 1826,8 and the first semi-synthetic pure drugaspirin (2), based on a natural product salicin (3) isolated from Salix alba,was introduced by Bayer in 1899. This success subsequently led to theisolation of early drugs such as cocaine, codeine, digitoxin (4), quinine (5),and pilocarpine (6), of which some are still in use.7,8,86–88



Morphine (1) Aspirin (2) Salicin (3)

OH

H

NCH3

OHOOAc

COOH OCH2OH

O OHOH

OH

HO


3. Natural Products: The Inherent Potentiality

The most striking feature of natural products in connection to their long-lasting importance in drug discovery is their structural diversity that is stilllargely untapped. Most natural products are not only sterically more com-plex than synthetic compounds, but differ also with regards to thestatistical distribution of functionalities.89 They occupy a much larger vol-ume of the chemical space and display a broader dispersion of structuraland physicochemical properties than compounds issued from combinato-rial synthesis.90 It needs to be mentioned that in spite of massiveendeavors adopted in recent times for synthesizing complex structuresfollowing “diversity oriented synthesis” (DOS) strategy,91 about 40% ofthe chemical scaffolds found in natural products are still absent in today’smedicinal chemistry.92 The chemical diversity and unique biological

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O O

H

OH

H

H

HOO

OH

O

OH

O

OH

HO OO

Digitoxin (4)

Quinine (5)

N

N

H

HO

H

MeO

N

N

O

O

Pilocarpine (6)


activities of a wide variety of natural products have propelled many dis-coveries in chemical and biological sciences, and provided therapeuticagents to treat various diseases as well as offered leads for the develop-ment of valuable medicines.

The history of pharmacognosy is, in part, defined by the ever expand-ing catalog of naturally occurring, biologically active compounds thathave been discovered and characterized. It has been estimated that about40% of medicines have their origin in these natural products.52,93 Thechemical potential of plants is however, still largely unexplored. Chemicaldiversity has only been analyzed in about 5–15% of all land plants, andeven here only the most abundant compounds have been well character-ized. Hence, there remains an unprecedented possibility for the discoveryof novel chemicals that may find diverse uses from pharmaceuticalsthrough fine chemicals. Natural products, thus, continue to be a majorsource of biologically active compounds that may serve as commerciallysignificant entities themselves or may provide lead structures for thedevelopment of modified derivatives possessing enhanced activity and/orreduced toxicity.

Even though combinatorial synthesis is now producing molecules thatare drug-like in terms of size and property, these molecules, in contrast tonatural products, have not evolved to interact with biomolecules.94

Natural compounds such as brefeldin A, camptothecin, forskolin andimmunophilins often interfere with protein–protein interaction sites.95

Analysis of the properties of synthetic and natural compounds comparedto drugs revealed the distinctiveness of natural compounds, especiallyconcerning the diversity of scaffolds and the large number of chiral cen-tres. This may be one reason why ~50% of the drugs introduced to themarket during the last 20 years are derived directly or indirectly from nat-ural compounds.97

In chemical biology, natural products play an important role to eluci-date complex cellular mechanisms, including signal transduction and cellcycle regulation, leading to the identification of important targets for ther-apeutic intervention.56,98 There has been an increasing demand for newnatural products, or new natural product-like small molecules in thefields of genomic and proteomics for the rapid identification of largenumbers of gene products for which the small molecule modulators will




be of both biological and medicinal interest.99–103 Besides, the combina-tion of cell biology and high throughput technology has led to thedevelopment of various cellular assays in which small molecule librariescan be used to identify and study previously known targets.104

The reason for the lack of lead compounds from synthetic libraries insome therapeutic areas such as anti-infectives, immunosuppression,oncology, and metabolic diseases may be due to the different chemicalspace occupied by natural products and synthetic compounds.89,90,92,105

This difference in chemical space makes natural products an attractivealternative to synthetic libraries, especially in therapeutic areas that havea dearth of lead compounds. Natural products have been used also as start-ing templates in the synthesis of combinatorial libraries.92,106–110 Naturalproduct pharmacophores are well represented in lists of “privileged struc-tures”, which make them ideal candidates for building blocks forbiologically relevant chemical libraries.111,112 Natural products still con-stitute a prolific source of novel lead compounds or pharmacophores formedicinal chemistry, and hence, natural products should be incorporatedinto a well-balanced drug discovery program. Besides their potential aslead structures in drug discovery, natural products also provide attractivescaffolds for combinatorial synthesis and act as indispensable tools for thevalidation of new drug targets.113

4. Natural Products in Drug Discovery: Success, Constrainsand New Approaches for Remedies

4.1. A Success Story

Mother Nature still continues to be a resource of novel chemotypes andpharmacophores, and an impressive number of modern drugs have beenisolated from natural sources, many based on their uses in traditional med-icine systems.33–35,114 To a large extent, the use of natural products in drugdesign represents the natural evolution of this old tradition. It has beenextensively documented that the traditional medicine systems of manycultures worldwide are based on plants,38,113,115–118 for example in coun-tries like China33 and India35 where plants have formed the basis fortraditional systems of medicines. According to Kim and Park,119 natural

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products have been regarded as important sources that could producepotential chemotherapeutic agents. A comprehensive review of the historyof medicine may be consulted, in this regard, on the homepage of theNational Library of Medicine (NLM), History of Medicine atwww.nlm.nih.gov/hmd/hmd.html.

Large numbers of promising lead molecules have come out ofAyurvedic experimental base including Rauwolfia alkaloids for hyperten-sion, psoralens in vitiligo, guggulsterons as hypolipidemic agents,Mucuna pruriens for Parkinson’s disease, bacosides in mental retention,phyllanthus as antivirals, picrosides in hepatic protection, curcumines ininflammations, withanolides and many others steroidal lactones and gly-cosides as immunomodulators;24,120 plants have thus, always been a richsource of natural product leads — a few more examples are: morphine,cocaine, digitalis, quinine, tubocurarine, nicotine, muscarine, paclitaxel(Taxol™) and artemisinin. There are growing evidences where the oldmolecules are finding new applications through better understanding oftraditional knowledge and clinical observations. For instance, the alka-loid, forskolin isolated by Hoechest and coleonol by Central DrugResearch Institute (CDRI), Lucknow, India a few decades ago fromColeus forskohlii121 and phytochemicals from Stephania glabra, whichwere shelved for a considerable time are now being rediscovered asadenylate cyclase and nitric oxide activators, which may help in prevent-ing conditions including obesity and atherosclerosis.122 Natural productsalso provide a vast pool of pancreatic lipase inhibitors as potential candi-dates, which can be developed into new drugs for the treatment ofconditions like obesity.123 A large number of promising leads for thedevelopment of newer anti-inflammatory drugs are also available inmedicinal plants.124

The blossoming of natural product discovery efforts occurred after thelarge scale production of penicillin during World War II, when the phar-maceutical companies that contributed to the war-time efforts to build stocksof penicillin refocused their programs on the search for new antibioticsfrom microorganisms.50 Mining of the bacterial genome and identifica-tion of crucial targets followed by study of new bacterial or fungal strainshave resulted in the discovery of significant antibacterial agents such ascephalosporins, streptomycin, gentamicin, tetracycline, chloramphenicol,




aminoglycosides, rifamycins and many others that spurred the industry todevelop large research and development programs around natural productdiscovery, particularly microbial fermentation-based technologies.125,126

All of the major pharmaceutical companies had programs on natural prod-uct discovery, and these programs focused not only on anti-bacterial andanti-fungal targets, but also on targets other than infectious diseases. In the1970s for example, the discovery of cholesterol biosynthesis-inhibitingdrugs compactin127,128 and mevinolin (a fungal metabolite isolated fromcultures of Aspergillus terreus)129,130 led to the development of the hugelysuccessful statin therapeutics, which even today represent successes inboth medical treatment and in pharmaceutical business fortunes.131–134

Since the past five decades, marine sources (viz. coral, sponges, fish andmarine microorganisms) have attracted scientists from different disci-plines leading to the discovery of several marine natural products withpromising biological activities; a few of them include curacin A, eleuther-obin, discodermolide, bryostatins, dolostatins, and cephalostatins.78,135

Venoms and toxins (peptides and non-peptides) found in snakes, spiders,scorpions, insects, and other microorganisms are also significant in drugdiscovery due to their specific interactions with macromolecular targets inthe body, and have been proven crucial while studying receptors, ionchannels, and enzymes. Toxins like α-bungarotoxin (from the venom ofthe elapid snake Taiwanese banded krait (Bungarus multicinctus)),136,137

tetrodotoxin (from puffer fish and many other widely varying animalsincluding certain bacteria)138–143 and teprotide (from Brazilian viper)144

etc. are in clinical trials for drug development. Similarly, neurotoxinsobtained from Clostridium botulinum (responsible for botulism, a seriousfood poisoning), were been found to be significant in preventing musclespasm.145

The impact of natural products on drug discovery has, thus, been enor-mous; natural products originating from microorganism, plant and animalsources have been the single most productive source of leads for the devel-opment of drugs to treat human diseases9,48,52 More than 80% of drugsubstances involved in drug discovery programs in “olden times” (i.e.before the advent of high-throughput screening (HTS) and the post-genomicera) were reported to be natural products or inspired by natural productstructures.87,113 It is arguably still true; comparisons of the information

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presented on sources of new drugs from 1981 to 200751,72 indicate thatalmost half of the drugs approved since 1994 are based on natural products.In the areas of cancer and infectious diseases, 60% and 75% of new drugs,respectively, originated from natural sources between 1981 and 2002.52

Between 2001 and 2005, 23 new drugs derived from natural products wereintroduced for the treatment of disorders such as bacterial and fungal infec-tions, cancer, diabetes, dyslipidemia, atopic dermatitis, Alzheimer’s diseaseand genetic diseases such as tyrosinaemia and Gaucher disease; two drugshave been approved as immunosuppressive agents and one for pain man-agement. Thirteen natural product-related drugs were approved from 2005to 2007 and, as pointed out by Butler, five of these represented the firstmembers of new classes of drugs:72 the peptides exenatide and ziconotide,and the small molecules ixabepilone, retapamulin and trabectedin.146 Of the90 antibacterial drugs that became commercially available in the US or wereapproved worldwide from 1982 to 2002, ~79% can be traced to a naturalproduct origin.52 According to a study by Grifo and his colleagues,147 84 of arepresentative 150 prescription drugs (prescribed mainly as anti-allergy/pulmonary/respiratory agents, analgesics, cardiovascular drugs, and forinfectious diseases) in the US were natural products and related drugs.Another study found that natural products or related substances accountedfor 40%, 24%, and 26% of the top 35 worldwide ethical drug sales in 2000,2001, and 2002 respectively.9 Of these natural product-based drugs, pacli-taxel (ranked at 25 in 2000), a plant-derived anticancer drug, had sales of$1.6 billion in 2000.148,149 The sales of two categories of plant-derived can-cer chemotherapeutic agents were responsible for approximately one thirdof the total anticancer drug sales worldwide, or just under $3 billion dollarsin 2002; namely, the taxanes, paclitaxel and docetaxel, and the camptothecinderivatives, irinotecan and topotecan.148,149 In addition to this historical suc-cess in drug discovery, natural products are likely to continue to be sourcesof new commercially viable drug leads. Combined with pharmacologicalscreening, the chemistry of natural products has always provided highlyuseful leads for drug discovery. The search for new biologically active com-pounds are most often based on hints from ethnobotany but there are still alarge number of unstudied plants, mushrooms, marine organisms, insects,and microorganisms. There is a wealth of molecular diversity out there,waiting to be discovered and utilized.




4.2. Lacunae/Constrains

After very successful drug discovery and development programs based onnatural products, the pharmaceutical industry, in particular the large phar-maceutical companies, de-emphasized natural product discovery research inthe 1990s and early 2000s.27,60,146,150,151 This was caused by the advent ofalternative drug discovery methods such as rational drug design involvingautomated high-throughput screening (HTS) technology in combinationwith combinatorial chemistry152–159 with the belief and hope that newlydeveloped technologies would result in the development of drugs within ashort and affordable time scale of the so-called “blitz” screen (start to finishin 3 months). Thus, the promise of a ready supply of large synthetic com-pound libraries led many companies to eliminate or considerably scaledown their natural product operations.160–164 The major causative pointsthat directed the downfall of natural products in the pharmaceutical indus-try in the 1990s include difficulties in access and supply, complexities ofnatural product chemistry, the inherent slowness of working with naturalproducts, and concerns about intellectual property rights. Rediscovery ofknown compounds is a major problem when screening natural productlibraries. This is caused by a lack of efficient dereplication methodologiesfor both natural product sourcing and compounds in the natural productlibraries. The time-consuming processes of dereplication and purificationare not compatible with the present regime of “blitz” screening campaignsin which assay support is only available for a limited duration (3 months).Besides, natural products are often structurally complex; modification ofcomplex natural products using organic chemistry is frequently challenging.Medicinal and combinatorial chemists prefer not to work with natural prod-ucts because of the large size and complexity of the compounds, which havetoo many functional groups to protect. It is difficult to prepare as many nat-ural product analogs as synthetic chemicals in the same amount of time.47

However, despite the promise of these alternative drug discovery methods,there is still a shortage of lead compounds progressing into clinical trials.This is especially the case in therapeutic areas such as oncology, immuno-suppression and metabolic diseases where natural products have played acentral role in lead discovery. Marketed drugs derived from natural productsstill account for significant revenues in many of the major pharmaceuticalcompanies.165 Lipitor, zocor and pravachol, the cholesterol-regulating

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therapeutic agents derived from the natural product statin class of com-pounds, continue to generate multi-billion dollar revenues. Antibiotics, likezithromax and the generic penicillins, continue to be essential in medicalcare, however they contribute less to pharmaceutical revenues than non-antibiotics due to their relatively limited dosing intervals.

4.3. New Approaches for Possible Remedies

Recent technological advances and the development of new methods haverevolutionized the screening of natural products and offer a unique oppor-tunity to re-establish natural products as major source of drug leads. Thenew methods and technologies can address the aforementioned limitationsof the screening of natural products. Examples of recent advances in theapplication of these technologies that have immediate impact on the dis-covery of novel drugs are: (i) development of a streamlined screeningprocess for natural products, (ii) improved natural product sourcing,(iii) advances in organic synthetic methodologies, (iv) combinatorialbiosynthesis, and (v) microbial genomics. Each of these technologies wasdiscussed in details by Kin S. Lam in his article “New aspects of naturalproducts in drug discovery”.47 Approaches based on reverse pharmacologymay also offer efficient platforms for herbal formulations; the impact ofsuch approaches has recently been elaborately reviewed by Patwardhanand Vaidya.24 All these technologies at large have already shown an impacton the development of natural product leads arising out of varying naturalsources inducing microbial and marine environments. The biosynthesis ofnatural products themselves can also be manipulated with the understand-ing of the genetics and biosynthesis pathways to yield new derivatives withpossibly superior qualities and quantities.166,167 In addition to identifyingnew natural products, genome mining would certainly have an impact onthe understanding and manipulation of the production of natural products.

Natural product compounds not only serve as drugs or templates fordrugs, but in many instances lead to the discovery and better understand-ing of targets and pathways involved in the disease process. Elucidation ofthe anti-inflammatory mechanism of aspirin action led to the discovery ofthe cyclooxygenase isozymes COX-1 and -2, which are being used in thedevelopment of novel anti-inflammatory drugs.168 Again natural products




that interact with some other novel targets, such as the protein–proteincomplexes B-catenin in the WNT pathway and HIF-1/p300,169 have vali-dated these anticancer targets and pathways. Natural products also createopportunities for additional drug targets to be identified and exploited inthese pathways. Whereas synthetic drugs are typically the result of numer-ous structural modifications over the course of an extensive drug discoveryprogram, a natural product can go straight from “hit” to drug in many sit-uations. Microbial natural products are notable not only for their potentialtherapeutic activities, but also for the fact that they frequently have thedesirable pharmacokinetic properties required for clinical development.Antibacterial agents erythromycin A, vancomycin, penicillin G, strepto-mycin and tetracycline, antifungal agents amphotericin B and griseofulvin,the cholesterol-lowering agent lovastatin, anticancer agents daunorubicin,mitomycin C and bleomycin, and immunosuppressants rapamycin,mycophenolic acid and cyclosporine A are just a few of the many micro-bial natural products that reached the market without requiring anychemical modifications. These examples clearly demonstrate the remark-able ability of microorganisms to produce drug-like small molecules.47

5. Drug Discovery, Development and Approval Processes

The final launching of a natural product (NP)-based drug in the market is amulti-step phenomena starting from its discovery stage.170 Bioactivity-guided screening followed by isolation and characterization of a NP-leadmolecule is the first step; after that the NP-lead enters into the drug discov-ery stage involving target identification and lead optimization. Leadoptimization is an outcome of various steps including analysis (also involvesQSAR and molecular modeling), design, synthesis and screening. In the drugdiscovery and development stages, the pharmacokinetics and pharmacody-namics including absorption, distribution, metabolism, excretion, andtoxicity (ADMET) for the test drug molecule are thoroughly investigated.After analyzing all these data, the drug molecule may enter into the finaldevelopment stage for drug delivery that involves proper production formu-lation, which is eventually considered for clinical trials. The whole processmay be summarized in the flowchart (Fig. 1).170 Lead identification and opti-mization (involving medicinal and combinatorial chemistry), lead

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Bioactivity-Guided Screening,Isolation and Characterizationof Natural Products (NPs)

Discovery ofNP-Lead

LeadOptimization

Rational Drug Design-Based Analog Synthesis

TargetIdentification

Drug DiscoveryStage

ADMETDrug Development

Stage(Product Formulation)

Clinical TrialStage

Approval Processes

Launching of the drug on the market,after successful clinical trials followedby proper approvals

Fig. 1. Flowchart for drug discovery, development and approval of a natural product-based drug.

development (including pharmacology, toxicology, pharmacokinetics,absorption, distribution, metabolism, and excretion (ADME) and drug deliv-ery), and clinical trials all take considerable time. It has been estimated thatthe process of drug discovery usually takes an average period of 10 years andcosts more than $800 million.151 Much of this time and money is spent onthe numerous leads that are discarded during the drug discovery process. Itis also estimated that only 1 in 5000 lead compounds will successfullyadvance through clinical trials and be approved for use.

For approval and marketing of a new drug, certain processes are to befollowed: first, the Investigational New Drug (IND) application is sub-mitted to the US Food and Drug Administration (FDA) or EuropeanMedicines Agency (EMEA) before commencement of clinical trials. Onceclinical trials are successfully completed, the applicant files for a NewDrug Application (NDA) in the US or Marketing Authorization Application(MAA) in Europe seeking the drug’s approval for marketing, to which theagency replies in the form of an “approval letter”, “non-approval letter”or “approvable letter”. An “approval letter” allows the applicant to beginmarketing of product, while a “non-approval letter” rejects the applica-tion. An “approvable letter” informs the applicants that the agency havecompleted their scientific review and determined that the application canbe approved pending resolution of minor deficiencies identified in the let-ter or during an inspection of the manufacturing facilities.




6. Natural Product-Based Drugs Approved During 2000–2010

A total of about 38 natural product-based drugs were approved andlaunched in the market during the period 2000 to 2010. This section dealswith these approved drugs as per categorized diseases areas such as infec-tious disease area (15 drugs), oncology (7 drugs), neurological diseasearea (7 drugs), cardiovascular and metabolic disease area (4 drugs), dia-betes (1 drug), and some other diseases areas (4 drugs). In addition, allthese approved drugs are summarized in Table 1.

6.1. Infectious Disease Area

6.1.1. Arteether

Arteether (7; Artemotil®, Artecef ®), the semi-synthetic derivative ofartemisinin (8), is a potent antimalarial drug. Artemisinin, a naturalendoperoxide sesquiterpene lactone, is the active chemical constituent ofArtemisia annua L. (Asteraceae), a plant used in traditional Chinesemedicine.171–176 Arteether belongs to the first-generation of artemisininanalogs obtained by derivatization at C-10, and such semi-synthetic deriv-atives were proved to be extremely active and more potent than the parentcompound, acting rapidly as blood schizontocidal agent against the para-site’s (Plasmodium falciparum) asexual erythrocytic (red blood cell) stageas well as against the parasite blood-stage gametocytes (sexual stage),which can potentially help to reduce the rate of malaria transmission.177,178

Other derivatives of artemisinin are in various stages of clinical develop-ment as antimalarial drugs in Europe.54,172

18 Brahmachari


Arteether (7)

O

OO

O

H

H

O

O

OO

O

H

H

O

Artemisinin (8)


Natural P

roducts in Drug D

iscovery19

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ioactive Natural Products

Table 1. Natural product (NP)-derived drugs launched since 2000 by year with reference to their lead compound, classification, thera-peutic area and mechanism of action.

Generic name Producing(Str. No.; trade Lead compound Compound organism/ Disease area/

Year name) (Str. No.) class Classification Origin Indication Mechanism of action Reference

2000 Arteether (7; Artemisinin (8) Endoperoxide Semi-synthetic Plant Antimalarial Acts as blood 54, 171–179Artemotil®, sesquiterpene NP schizontocidal agentArtecef®, lactone against the parasite’sE-Mal®) asexual erythrocytic

(red blood cell) stageand also against theparasite blood-stagegametocytes (sexualstage)

2000 Gemtuzumab Calicheamicin Enediyne-type NP-derived Microbial Anticancer DNA-cleaving 319–331ozogamicin (30; (31) antibioticMylotarg®)

2000 Bivalirudin (55; Hirudin Peptide Synthetic Animal Antithrombotic Specific and reversible 479–491Angiomax®) congener direct thrombin

inhibitor (DTI)

2001 Caspofungin Pneumocandin B0 Lipopeptide Semi-synthetic Microbial Antifungal Inhibits fungal cell wall 180–186acetate (9; NP synthesisCancidas®)

2001 Ertapenem (10; Thienamycin (11) Carbapenem NP-derived Microbial Antibacterial Inhibits bacterial cell 187–197Invanz®) antibiotic wall synthesis

2001 Cefditoren pivoxil Cephalosporin β-Lactum NP-derived Microbial Antibacterial Inhibits bacterial cell 198–200(12, Spectracef ®) antibiotic wall synthesis

(Continued )


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Table 1. (Continued )



2001 Pimecrolimus (58; Ascomycin Macrolactum Semi-synthetic Microbial Inflammatory Blocks T-cell activation 505–517Elidel®) antibiotic NP skin diseases

and atopicdermatitis

2002 Biapenem (14; Thienamycin (11) Carbapenem- NP-derived Microbial Antibacterial Inhibits bacterial cell 201–210Omegacin®) type wall synthesis

β-lactum

2002 Amrubicin Doxorubicin (33) Anthraquinone NP-derived Microbial Anticancer Inhibits topoisomerase II 208–210,hydrochloride 332–336(32; Calsed®)

2002 Nitisinone (59; Leptospermone 2-[2-Nitro-4- NP-derived Plant Antityrosinaemia Inhibits 208–210,Orfadin®) (trifluoromethyl) p-hydroxyphenyl- 518–524

benzoyl] pyruvate dioxygenasecyclohexane- (HPPD) activity1,3-dione

2002 Galantamine Galantamine (42) Alkaloid NP Plant Alzheimer’s Inhibits the activity of 393–402hydrobromide disease acetylcholinesterase(43; Reminyl®) (AChE)

2003 Daptomycin (15; Daptomycin (15) Lipopeptide NP Microbial Antibacterial Disrupts multiple 211–225CubicinTM) aspects of bacterial

cell membranefunction

(Continued )


Natural P

roducts in Drug D

iscovery21

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2003 Miglustat (60; 1-Deoxynojirimycin Iminosugar Semi-synthetic Microbial Type 1 Gaucher Inhibits 215–217,Zavesca®) (DNJ) NP disease (GD1) glucosylceramide 525–531

synthase activity

2003 Mycophenolate Mycophenolic acid Fatty acid NP Microbial Immuno- Inhibits inosine 215–217,sodium (62; (61) antibiotic suppression monophosphate 532–560Myfortic®) dehydrogenase

(IMPDH) activity

2003 Rosuvastatin Mevastatin Statin NP-derived Microbial Dyslipidemia Inhibits the rate-limiting 215–217, calcium (56; step in the formation 492–495Crestor®) of endogenous

cholesterol by HMG-CoA reductase

2004 Telithromycin Erythromycin A 14-Membered Semi-synthetic Microbial Antibacterial Blocks bacterial 181, 182,(16; Ketek®) macrolide NP polypeptide chain 183,

growth 226–230

2004 Apomorphine Morphine (43) Alkaloid Semi-synthetic Plant Parkinson’s Potent dopamine 403–416hydrochloride NP disease receptor agonist(44; Apokyn®)

2004 Ziconotide (45; Ziconotide (45) Peptide NP Animal Pain Acts as a selective 417–428PrialtTM) N-type voltage-gated

calcium channelblocker

(Continued )


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2004 Tiotropium Atropine Alkaloid Semi-synthetic Plant Chronic Inhibits M3 muscarinic 475–478bromide (54; NP obstructive receptorsSpiriva®) pulmonary

disease(COPD)

2005 Tigecycline (19, Tetracycline (17) Tetracyclines Semi-synthetic Microbial Antibacterial Inhibits bacterial protein 231–238Tygacil®) NP translation

2005 Doripenem(20; Thienamycin (11) Carbapenem-type NP-derived Microbial Antibacterial Inhibits bacterial cell 239–247Finibax®/ β-lactum wall growthDoribaxTM)

2005 Micafungin (21; FR901379 Macrocyclic Semi-synthetic Microbial Antifungal Inhibits fungal cell wall 186,Mycamine®/ lipopeptido- NP synthesis 208–210,Funguard®) lactone 248–260

2005 Fumagillin (22; Fumagillin (22) Antibiotic NP Microbial Antiparasitic Inhibits intestinal 261–278Flisint®) microsporidiosis

2005 Dronabinol (46)/ Dronabinol (46)/ Cannabinoids NPs Plant Pain Suppresses 429–438Cannabidol Cannabidol (47) neurotransmitter(47) (Sativex®) release

2005 Zotarolimus (53; Sirolimus (33) Macrolide Semi-synthetic Microbial Cardiovascular Inhibits cell 467–474EndeavorTM antibiotic NP surgery proliferation,stent) preventing scar tissue

formation andminimizes restenosisin angioplasty patients

(Continued )


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roducts in Drug D

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2006 Anidulafungin (23; Echinocandin B (24) Lipopeptide Semi-synthetic Microbial Antifungal Inhibits fungal cell wall 279–293EraxisTM/ antibiotic NP synthesisEcaltaTM)

2006 Exenatide (57; Exenatide-4 (57) A 39-amino-acid NP Animal Diabetes Enhances glucose- 496–504ByettaTM) peptide dependent insulin

secretion by thepancreatic β-cells,suppressesinappropriatelyelevated glucagonsecretion, and slowsgastric emptying

2007 Retapamulin (26; Pleuromutilin (25) Antibiotic Semi-synthetic Microbial Antibacterial Inhibits bacterial protein 294–303AltabaxTM/ NP (topical) synthesisAltargoTM)

2007 Temsirolimus (35; Sirolimus (34) Macrolide Semi-synthetic Microbial Anticancer Leads to cell cycle 337–350ToriselTM) antibiotic NP arrest in the G1 phase,

and inhibits tumorangiogenesis byreducing synthesis ofvascular endothelialgrowth factor (VEGF)

(Continued )


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2007 Trabectedin (36; Trabectedin (36) Tetrahydro- NP Ascidian Anticancer Inhibits cell 351–362YondelisTM) isoquinoline (marine proliferation by

alkaloid animal) disrupting the cellcycle

2007 Ixabepilone (40; Epothilone B (38) Macrolide NP-derived Microbial Anticancer Binds directly to β- 363–374IxempraTM) antibiotic tubulin subunits on

microtubules,ultimately leading tocell death

2007 Lisdexamfetamine Amphetamine (49) Amine NP-derived Plant Attention deficit Increases the release of 439–448(48; Vyvanse®) hyperactivity amphetamine-type

disorder monoamines into the(ADHD) extraneuronal space,

thereby improving theeffect of ADHD

2008 Methylnaltrexone Naltrexone (51) Alkaloid NP-derived Plant Opioid-induced Blocks peripheral opioid 449–459(50; Relistor®) constipation receptors, and acts as

and pain an antagonist

(Continued )


Natural P

roducts in Drug D

iscovery25

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2009 Capsaicin (52; Capsaicin (52) Vanilloid NP Plant Pain Binds to the ion channel 460–466Qutenza®) receptor vanilloid

receptor subtype 1(VR 1)

2009 Telavancin (28; Vancomycin (27) Antibiotic Semi-synthetic Microbial Antibacterial Inhibits bacterial cell 304–311VibativTM) NP wall synthesis

2009 Everolimus (40; Sirolimus (34) Macrolide Semi-synthetic Microbial Anticancer Inhibits mTOR kinase 375–382Afinitor®) antibiotic NP activity

2009 Romidepsin (41; Romidepsin (41) Depsipeptide NP Microbial Anticancer Inhibits histone 383–392Istodax®) deacetylase (HDAC)

2010 Aztreonam lysine Aztreonam (29) Monobactam NP-derived Microbial Antibacterial Inhibits bacterial cell 312–318(29; CaystonTM) antibiotic wall synthesis


The central Drug Research Institute (CDRI) in collaboration withCIMAP (Central Institute of Medicinal and Aromatic Plants), Lucknow, Indiahave also conducted extensive clinical trials with arteether that was found notonly to be very safe but also proved to be a fast-acting blood schizontocidalagent. CDRI has licensed the drug to Themis Chemicals Ltd., Mumbai whichis marketing it under the trade name “E-Mal®” as an injectable formulation.The Drugs Controller General (India) has allowed the use of the drug exclu-sively in hospitals and nursing homes. The drug is indicated for use only insevere P. falciparum-induced-malaria including cerebral malaria as a second-line treatment for chloroquine-resistant cases. It is not recommended to beused as a first-line treatment against malaria to avoid against overuse, whichmay lead to the emergence of resistance against this drug once again.179

6.1.2. Caspofungin acetate

Caspofungin acetate (9; Cancidas®, Merck, 2001) is a semi-syntheticantifungal lipopeptide compound derived from pneumocandin B0, afermentation product of Glarea lozoyensis. The drug inhibits the synthe-sis of the glucose homopolymer β-(1,3)-D-glucan, an essential component

26 Brahmachari


N

N

HO

HO

OH

NH

O

O

NH

OH

O Me

OHHN

O

NH NH

OOH

OHO

O

H2N

HO

NH

H2N

2CH3COOH

Caspofungin (9)


of the cell wall of many fungi but absent in mammals. The noncompeti-tive inhibition of β-(1,3)-D-glucan synthase by caspofungin interfereswith fungal cell wall synthesis, leading to osmotic instability and death ofthe fungal cell.180–184

6.1.3. Ertapenem

Ertapenem (10; Invanz™, Merck, 2001) is a new 1β-methylcarbapenemantibiotic derived from thienamycin (11), isolated from Streptomyces catt-leya.181,187–191 The drug shows promising broad-spectrum antibacterialactivity against both Gram-positive and Gram-negative bacteria, such asclinically relevant Enterobacteriaceae including Escherichia coli, Klebsiellaspecies, Citrobacter species, Enterobacter species, Morganella morganii,Proteus species, and Serratia marcescens.190,192–195 Ertapenam is licensedfor use in adults and has been marketed by Merck as “Invanz™” since2001; later in 2005, it was licensed for use in children of more than3 months of age. The antibiotic inhibits bacterial cell wall synthesis by bind-ing to specific penicillin-binding proteins (PBPs). It is highly stable againstmost β-lactamases including AmpC β-lactamases and extended-spectrumβ-lactamases with the exception of metallo-β-lactamases.190,195–197



NH

N

O

OH

H

H

S

O

NH

HOO

O

O

H

Na+ −

Ertapenem (10)

N

O

OH

H

H

S

HO

O

NH2

Thienamycin (11)

6.1.4. Cefditoren pivoxil

Cefditoren pivoxil (12; Spectracef ®; TAP Pharmaceuticals, 2001) is anoral prodrug of cefditoren (13), a derivative of cephalosporin isolated fromCephalosporium species. The prodrug is readily hydrolyzed by intestinalesterases to the microbiologically active cephalosporin cefditoren (13)


28 Brahmachari


H S

N

S

N

O

OO O

O

NH

O

N OMe

S

NH2N

H

Cefditoren pivoxil (SpectracefTM) (12)

3

Esterase

H S

N

S

N

O

OO OH

NH

O

N OMe

S

NH2N

H 3

(hydrolysis)

−HCHO

H S

N

S

N

O

OHO

NH

O

N OMe

S

NH2N

H 3

Cefditoren (13)


exhibiting a broad spectrum of activity against both Gram-positive andGram-negative bacteria, and is stable to hydrolysis in the presence of avariety of β-lactamases. Cefditoren pivoxil is approved for use in thetreatment of acute exacerbations of chronic bronchitis (AECB), mild-to-moderate community-acquired pneumonia (CAP), acute maxillarysinusitis, acute pharyngitis/tonsillitis, and uncomplicated skin and skinstructure infections in adult and adolescent patients. Thus, cefditorenpivoxil is a good option for the treatment of adult and adolescent patientswith specific respiratory tract or skin infections, particularly if there isconcern about Streptococcus pneumoniae with decreased susceptibility topenicillin, or β-lactamase-mediated resistance among the common com-munity-acquired pathogens.198–200

Cefditoren bears a 2-aminothiazole methoxime ring that has been foundto be responsible for its Gram-negative activity, while the methylthiazole-substituted vinyl group at C-3 offers antibacterial activity againstGram-positive bacteria. It has been observed that the hydrophilic carboxylgroup of the parent drug makes cefditoren orally inactive due to poor per-meation across the intestinal mucosa; hence, esterification of the polarcarboxyl group increases lipophilicity and allows intestinal absorption tooccur. That is, cefditoren pivaloyl methyl ester (12) is not biologicallyactive, but after absorption, esterases readily hydrolyze the prodrug to thebiologically active cefditoren (13).200

6.1.5. Biapenem

Biapenem (14; Omegacin®; Wyeth Lederle Japan, 2002) is a new ana-log of carbapenem based on thienamycin, isolated from Streptomycescattleya; the antibacterial drug is found to be effective against bothGram-negative and Gram-positive bacteria including the species thatproduce β-lactamases. The early carbapenems (e.g. imipenem) areunstable to hydrolysis by human renal dihydropeptidase (DHP)-Iand require co-administration with a DHP-I inhibitor (e.g. cilastatin).On the contrary, biapenem (14) is found to be more stable to hydroly-sis by human renal DHP-I than imipenem, meropenem, and panipenem,and can thus be administered as a single agent without a DHP-Iinhibitor.201–210




6.1.6. Daptomycin

Daptomycin (15; Cubicin™; Cubist Pharmaceuticals, 2003), a cycliclipopeptide antibacterial agent derived from Streptomyces roseosporus,was approved for the treatment of complicated skin and skin structureinfections (cSSSIs) caused by Gram-positive pathogens, includingvancomycin-resistant enterococci and methicillin-resistant Staphylococcusaureus and right-sided S. aureus endocarditis. Daptomycin has a uniquemechanism of action that results in the disruption of multiple aspects ofbacterial cell membrane function. It appears to bind to the membrane andcause rapid depolarization, resulting in a loss of membrane potential, leading

30 Brahmachari


N

O

OH

H

H

S

COO−

N

N

N+

Biapenem (14)

HN

HN

O

NH

O

O

NH

CONH2

O

NH

HOOC

H

O

O

NH

ONH2

O

NH

COOH

H

O

NH

OH

O

NHO

NH

COOH

O

NH

O

NH

O

COOH

NH

H2N

O

NH O

Daptomycin (15)


to the inhibition of protein, DNA and RNA synthesis, which results in bac-terial cell death. The rapid bactericidal activity of daptomycin makes it anattractive antibiotic for serious Gram-positive infections.211–225

6.1.7. Telithromycin

Telithromycin (16; Ketek®; Aventis, 2004) is a semi-synthetic derivativeof the 14-membered macrolide, erythromycin A, isolated from Saccharo-polyspora erythraea, and retains the macrolactone ring as well as aD-desosamine sugar moiety. It is the first approved ketolide, developed bySanofi-Aventis in Phases II/III trials in 1998, that received approval fromthe FDA in April 2004 against respiratory infections. The drug exhibits anantibacterial effect on respiratory tract pathogens resistant to othermacrolides. Telithromycin (16) displays bactericidal activity by blockingthe progression of the growing polypeptide chain by binding with the pep-tidyltransferase site of the bacterial 50S ribosomal subunit.180,181,183,226–230



O

OH

O

O

N

NNN

O

O

O O

O

MeO

Me2N

Telithromycin (16)

6.1.8. Tigecycline

Tigecycline (19, Tygacil®; Wyeth, 2005) is the 9-tert-butyl-glycylamidoderivative of minocycline (18), which is in turn semi-synthetically derived


from the natural product tetracycline (17) isolated from Streptomycesaureofaciens. It is among one of the new generation antibiotics known asglycylcyclines; it contains a centralized four-ring carbocyclic skeletonsubstituted at the D-9 position, thus conferring broad spectrum activity.Tigecycline exhibited antibacterial activity typical of other tetracyclines,but with more potent activity against tetracycline-resistant organisms.Tigecycline is only utilized in an injectable formulation for clinical use,unlike currently marketed tetracyclines that are available in oral dosageforms. The drug (19) connects with 30S ribosome and hinders amino-acyltRNA molecules moving to the A site of the ribosome, thus inhibiting pro-tein translation. Tigecycline (19) was developed by Wyeth and wasapproved in June 2005 by the FDA for use against intra-abdominal andcomplicated skin and skin structure infections (cSSSIs).231–238 Since May2006, tigecycline (19) has been approved in Europe and later in October2007, a supplemental NDA for community-acquired pneumonia (CAP) tothe FDA was submitted.72

6.1.9. Doripenem

Doripenem (20; Finibax®/Doribax™; Shionogi Co. Ltd., 2005; Johnson &Johnson, 2007), a synthetic carbapenem-type β-lactam, has appeared to bean ultra-broad spectrum injectable antibiotic. It was launched in Japan byShionogi Co. Ltd. in the year 2005 as a broad antibacterial spec-trum.239–243 In October 2007, Johnson & Johnson (J&J) (formerly PeninsulaPharmaceuticals) obtained formal FDA approval for the use of doripenem

32 Brahmachari


NH

OH

OH

O

NH2

OOH

H

OOH

HO

Tetracycline (17)Minocycline (18): R = H

Tigecycline (19): R =

NH

OH

OH

O

NH2

OOH

H

OOH

N

R

NH

NH

O


(20) in intra-abdominal and urinary tract infections, including pyeloneph-ritis.244,245 When doripenem is absorbed into the body, the drug takeseffect by eliminating the initial bacteria causing the infection. Primarily,doripenem decreases the process of cell wall growth, which eventuallyleads to elimination of the infectious cell bacteria altogether. The use ofdoripenem (20) for treatment of hospital-acquired (nosocomial) pneumo-nia (HAP) is under FDA review, while in Europe, treatment of HAP andcomplicated urinary tract infections are under review.72,246,247

6.1.10. Micafungin

Micafungin (21; Mycamine®/Funguard®; Astellas Pharma/Fujisawa, Japan,2002, 2005), is a semi-synthetic derivative of FR901379 that was firstlaunched by Fujisawa in Japan in 2002 as a potent antifungal agent.208–210

This echinocandin-type compound exhibited good antifungal activityagainst a broad range of Candida species, including azole-resistant strains,and Aspergillus species, during in vitro and animal studies.186 Micafungin isindicated for the treatment of candidemia, acute disseminated candidiasis,candida peritonitis, abscesses and esophageal candidiasis.248–251 It receivedfinal approval from the US Food and Drug Administration on March 2005and gained approval in the European Union on April 25, 2008. The drug(21) inhibits the production of 1,3-β-D-glucan, an essential polysaccharidecomponent of fungal cell wall; this decreased glucan production leads toosmotic instability and thus cellular lysis;248–260 since January 2008, mica-fungin has been approved for the prophylaxis of Candida infections inpatients undergoing hematopoietic stem cell transplantation.



NH

NS

NH

SNH2

O O

H

H

H

O

OH

H

OOH

Doripenem (20)


6.1.11. Fumagillin

Fumagillin (22; Flisint®; Sanofi-Aventis, 2005) was first isolated in 1949from Aspergillus fumigatus261 and used shortly thereafter to treat intes-tinal amoebiasis;262–264 this antimicrobial agent is capable of inhibitingthe proliferation of endothelial cells. In September 2005, France approvedthe use of fumagillin (22) as a potent antibiotic against intestinalmicrosporidiosis; this is a disease caused by the spore-forming unicellularparasite Enterocytozoon bieneusi, which is of major concern to immuno-compromised patients as it can cause chronic diarrhea.265–273 In addition,semi-synthetic derivatives of fumagillin (22) with anti-angiogenic activityhave undergone clinical evaluation for the treatment of cancer.72

Fumagillin can block blood vessel formation by binding to an enzymecalled methionine aminopeptidase-2 (MetAP-2), and for this reason, thecompound, together with semi-synthetic derivatives, are investigated as

34 Brahmachari


O

ON

N

H2N NH

OO

NH

OH

OSO3Na

OH

HOOHO

HO

H

NH

O

HO

HO

NH

O

O

N

H

OH

O

NH

O

H

OH

Micafungin sodium (21; Mycamine®)


an angiogenesis inhibitor in the treatment of cancer and related diseaseareas.274–278

6.1.12. Anidulafungin

Anidulafungin (23; Eraxis™ in US/Ecalta™ in Europe, Pfizer, 2006), findsuse against invasive and esophageal candidiasis and candidemia;279–281

the drug is a semi-synthetic derivative of the fungal metaboliteechinocandin B (24).282 The drug was originally developed by Eli Lillyand licensed to Vicuron Pharmaceuticals, which was further purchased by



O

O

H

O

O

OMe

COOH

Fumagillin (22)

N

HN

NH

N

HOO

HO OH

O

NHHO

O

NH

R

O

OH

O

OH

NH

OOH

HO

HO

O

O

O

(23) R =

(24) R =

Anidulafungin (23); Echinocandin (24)


Pfizer in June 2005; Pfizer gained FDA approval in February 21, 2006(Eraxis™ in the US) and EMEA approval (Ecalta™ in Europe) in July2007.283–291 Anidulafungin inhibits enzyme complex 1,3-β-D-glucan syn-thase, thereby inhibiting fungal 1,3-β-D-glucan synthesis; this leads to thelysis of the fungal cell wall, and cell death.292,293 Glucan synthase is notpresent in mammalian cell walls and therefore is an attractive target forantifungal activity.

6.1.13. Retapamulin

Retapamulin (26; Altabax™ in the US and Altargo™ in Europe;GlaxoSmithKline, 2007) received FDA approval in April 2007 and theEuropean Medicines Agency (EMEA) approval in June 2007 for its topicaluse as 1% retapamulin ointment against bacterial infections.294–297 The drugis a semi-synthetic derivative of the fungal metabolite pleuromutilin (25),the first among pleuromutilin antibiotics developed by GlaxoSmithKline fortopical treatment of impetigo caused by Gram-positive Staphylococcusaureus or Streptococcus pyogenes.294–301 Pleuromutilin (25) was found tobind to peptidyl transferase and exhibits antibacterial activity by inhibit-ing protein synthesis in bacteria.302,303 Retapamulin (26) also exerts itsantibacterial potential specifically as a protein synthesis inhibitor. Themedication selectively inhibits bacterial protein synthesis by interacting at

36 Brahmachari


O

HO

O

R

OH

Pleuromutilin (25): R = OH

Retapamulin (26): R = NCH3S


a site on the 50S subunit of the bacterial ribosome through an interactionthat differs from other antibiotics.296,297,301

6.1.14. Telavancin

Telavancin (28; Vibativ™; Theravance/Astellas Pharmaceuticals, 2009),was discovered by Theravance as an antibacterial agent, and was devel-oped in partnership with Astellas.304–307 Telavancin (28), a semi-syntheticderivative of vancomycin (27), inhibits bacterial growth by binding to



Vancomycin (27) R1 = R2 = H

O

OO

Cl

ONH

HO

HO

O

NH

O

NH

O

OH

NH

NH

O

O

NH2

O

NH

O

NH

OH

Cl

HNOH

OH

OH

OH

O

O

OH

HO

R1

R2

NH

NH

PO(OH)2

R1 =

R2 =

Telavancin (28):


bacterial peptidoglycan precursors termini, D-Ala-D-Ala; it shows dualmode of action though disruption of plasma barrier membrane functionsby depolarization in addition to inhibition of cell wall synthesis.308

Theravance submitted an NDA in December 2006 and an MAA in May2007 for the use of telavancin (28) against Gram-positive complicatedskin and skin structure infections (cSSSIs) and methicillin-resistantStaphylococcus aureus (MRSA) that was approved in September 2009 bythe FDA.309–311 Theravance also submitted telavancin (28) to the FDA ina second indication against nosocomial pneumonia or hospital-acquiredpneumonia (HAP). In November 2009, the FDA released a completeresponse letter to Theravance for telavancin (28) NDA against nosocomialpneumonia.311

6.1.15. Aztreonam lysine

Aztreonam lysine (29; Cayston™; Gilead Sciences, 2010), an inhaledlysine salt formulation of monobactam aztreonam, has been evaluated byGilead in various Phase III trials against cystic fibrosis (CF) patients hav-ing a pulmonary infection of the Gram-negative bacteria Pseudomonasaeruginosa.312–317 In February 2010, the FDA approved the use ofTemsirolimus (35) in CF patients, however its safety and efficacy is yet tobe established in pediatric patients or Burkholderia cepacia colonized

38 Brahmachari


N

NH

O S

O

OO

N

N

S

H2N

O

COOH

OH

Aztreonam (29)


patients.318 Aztreonam binds to penicillin-binding proteins of susceptiblebacteria, leading to the inhibition of bacterial cell wall synthesis and celldeath.

6.2. Oncology

6.2.1. Gemtuzumab ozogamicin

Gemtuzumab ozogamicin (30; Mylotarg®; Wyeth, 2000), the first andapproved antibody–anticancer conjugate, was co-developed by Wyethand UCB Pharma and launched in 2000 for the treatment of refractoryacute myeloid leukaemia.319–326 Gemtuzumab ozogamicin (30) consistsof N-acetyl-calicheamicin dimethyl hydrazide (CalichDMH), a deriva-tive of the enediyne natural product calicheamicin (31), linked througha pH-labile hydrazone moiety to a recombinant humanized IgG4 k anti-body. Mylotarg®, a prodrug of calicheamicin bound to the anti-CD33monoclonal antibody, is cleaved by lysosomes in the cells to releasecalicheamicin. Calicheamicin is a hydrophobic member of the enediynefamily of DNA-cleaving antibiotics and is effective in the treatment of



OS

O

O

Me

I

O

OH

HO

Me

Me

OH

ONH

OMe

OMe

MeO

O

O

HO

Me

O

O

NMe

MeO

O

NH

O

Me

N NH

O

S

MeMe

S

OHO

NH

O

MeO

H

O

humanized IgG4 anti-CD33

Gemtuzumab ozogamicin (30)


patients with acute myeloid lymphoma.327–331 The calicheamicins (alsoknown as the LL-E3328 antibiotics) were discovered from fermenta-tion products produced by Micromonospora echinospora ssp.calichensis;331 calicheamicin (32) is an extremely potent cytotoxin thatbinds in the minor groove of DNA causing double strand DNA break-age.330,331 In the US, the drug was approved by the FDA in 2001 for usein patients over the age of 60 with relapsed acute myelogenousleukemia (AML), or those who are not considered candidates forstandard chemotherapy.320

6.2.2. Amrubicin hydrochloride

Amrubicin hydrochloride (33; Calsed®, Sumitomo PharmaceuticalsCo, 2002, Japan), a derivative of doxorubicin (34), isolated fromStreptomyces peucetius var caesius, showed activity comparable to thatof doxorubicin on transplantable animal tumors, including P388leukemia, sarcoma 180, and Lewis lung carcinoma, and exhibited morepotent antitumor activity against human tumor xenografts of breast,lung, and gastric cancer.208–210,332 The drug converts to its active form inthe body and acts as an inhibitor of topoisomerase II, thereby finding anapplication in the treatment of lung cancer.332–336 It has been marketedin Japan since 2002 by Sumitomo Pharmaceuticals under the brandname Calsed®.

40 Brahmachari


OS

O

O

Me

I

O

OH

OH

Me

Me

OH

ONH

OMe

OMe

MeO

O

O

HO

Me

O

O

NH

Me

MeO

S

OHO

NH

O

MeO

H

SMeS

Calicheamicin (31)


6.2.3. Temsirolimus

Temsirolimus (35; Torisel™, CCI-779; Wyeth, 2007), a semi-syntheticderivative of sirolimus (34), is an intravenous drug for the treatment ofrenal cell carcinoma (RCC)337–340 developed by Wyeth Pharmaceuticals



O

O

O

O

OH

OH

NH2

O

OHOH

Amrubicin (32)

O

O

O

O

OH

OHOMe

OH

O

OH

Me

OHNH

Doxorubicin (33)

OR

OMe

O

N

O

O

OO

OH

MeOO

O

HO

O

MeO

O

OH

OH

Sirolimus (34): R = H

Temsirolimus (35): R =


and approved by the US Food and Drug Administration (FDA) in May2007, and was also approved by the European Medicines Agency (EMEA)in November 2007. Sirolimus (34), a macrolide antibiotic, was first dis-covered as a product of the bacterium Streptomyces hygroscopicus in a soilsample from Easter Island.341 Temsirolimus (35) has been found to be aspecific inhibitor of mTOR (mammalian target of rapamycin) and inter-feres with the synthesis of proteins that regulate proliferation, growth, andsurvival of tumor cells.342–345 Treatment with temsirolimus leads to cellcycle arrest in the G1 phase, and also inhibits tumor angiogenesis by reduc-ing synthesis of vascular endothelial growth factor (VEGF).346–350

6.2.4. Trabectedin

Trabectedin (36; Yondelis™, ecteinascidin-743, ET-743; Zeltia andJohnson and Johnson, 2007), a tetrahydroisoquinoline alkaloid producedby the ascidian Ecteinascidia turbinate,351–356 received approval for itssale in Europe, Russia and South Korea by Zeltia and Johnson andJohnson under the brand name Yondelis™ for the treatment of advancedsoft tissue sarcoma (STS).357–358 Trabectedin (36) binds to the minor grooveof DNA and inhibits cell proliferation by disrupting the cell cycle.359,360

The biological mechanism of action is believed to involve the productionof superoxides near the DNA strand, resulting in DNA backbone cleavageand cell apoptosis. The actual mechanism is not yet known, but is believedto proceed from the reduction of molecular oxygen into superoxide via anunusual auto-redox reaction on a hydroxyquinone moiety of the com-pound following. There is also some speculation the compound becomes“activated” into its reactive oxazolidine form.

In September 2007, the EMEA approved the use of trabectidin againstovarian cancer (OC) and STS. In November 2009, Yondelis™ received itssecond marketing authorization from the European Commission for itsadministration in combination with pegylated liposomal doxorubicin(Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer;presently, trabectedin (36) is under Phase II trials for the treatment ofpaediatric sarcomas as well as breast and prostate cancers.72 The EuropeanCommission and the US Food and Drug Administration (FDA) havegranted orphan drug status to trabectedin for soft tissue sarcomas and

42 Brahmachari



ovarian cancer. Trabectedin (36) is produced commercially semi-synthet-ically from the eubacterium-derived cyanosafracin B (37).361,362

6.2.5. Ixabepilone

Ixabepilone (38; Ixempra™, BMS-247550; Bristol-Myers Squibb, 2007),a semi-synthetic derivative of epothilone B (39) produced by Sorangiumcellulosum, was developed by Bristol-Myers Squibb (BMS) as an anti-cancer drug (administered through injection) that binds directly toβ-tubulin subunits on microtubules, leading to suppression of microtubuledynamics, blocking of cells in the mitotic phase and ultimately leading to



Me

O

O

Me SO

NH

HO

MeO

O

N

NMe

OH

HO Me

OMe

H

O

O

Trabectedin (36)

O

N

NMe

OH

HO Me

OMe

O

MeO

Me

NH

O

Me

NH2

H

Cyanosafracin (37)

S

N

O

X

Me

Me

OH

OO OH

Ixabepilone (38): X = NHEpothilone B (39): X = O


cell death.363–368 In October 2007, the FDA approved ixabepilone, for thetreatment of aggressive metastatic or locally advanced breast cancers thatno longer respond to currently available chemotherapies, to be used as amonotherapy and as combination therapy with Xeloda against breast can-cer patients who are resistant to standard therapy.369–374

6.2.6. Everolimus

Everolimus (40; Afinitor®; Novartis, 2009), a rapamycin analog, is the 42-O-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as animmunosuppressant by Novartis under the tradename Afinitor® for use inadvanced renal cell carcinoma.375–378 In March 2009, the FDA approvedeverolimus (40) for use against advanced renal cell carcinoma after fail-ure of treatment with sunitinib or sorafenib.379 The drug works similarlyto sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), aserine–threonine kinase, downstream of the PI3K/AKT pathway. Everolimus(40) binds to an intracellular protein, FKBP-12, resulting in an inhibitory

44 Brahmachari


OMe

O

N

O

O

OO

OH

MeOO

O

HO

O

MeO

O OH

Everolimus (40)


complex formation and inhibition of mTOR kinase activity. Everolimusreduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryoticelongation factor 4E-binding protein (4E-BP), downstream effectors ofmTOR, involved in protein synthesis. In addition, everolimus (40) inhib-ited the expression of hypoxia-inducible factor (e.g. HIF-1) and reducedthe expression of vascular endothelial growth factor (VEGF). Inhibitionof mTOR by the drug has been shown to reduce cell proliferation, angio-genesis, and glucose uptake in vitro and/or in vivo studies. The spectrumof kinase inhibition, therefore its mechanism of anticancer activity, is differ-ent from that of Pfizer’s Sutent (sunitinib malate) or Onyx Pharmaceuticals’Nexavar (sorafenib).

Much research has also been conducted on everolimus and othermTOR inhibitors for use in a number of cancers. The FDA has recentlyapproved everolimus for organ rejection prophylaxis on April 22, 2010.380

A Phase II trial reports it is effective in the treatment of subependymalgiant cell astrocytomas (SEGA) associated with tuberous sclerosis.381 InOct 2010, the FDA approved its use in SEGA unsuitable for surgery.382 Asof Oct 2010 Phase III trials are under way in breast cancer, gastric cancer,hepatocellular carcinoma, pancreatic neuroendocrine tumors (NET), andlymphoma.382

6.2.7. Romidepsin

Romidepsin (41; Istodax®; Gloucester Pharmaceuticals, 2009), a naturallyoccurring histone deacetylase (HDAC) inhibitor obtained from the bacte-ria Chromobacterium violaceum,383–386 was developed and evaluated byGloucester Pharmaceuticals in various Phase I/II trials sponsored by theNational Cancer Institute (NCI) to use against cutaneous and peripheralT-cell lymphoma (TCL).387,388 In November 2009, romidepsin (41) wasapproved by the FDA under the trade name Istodax® against selectivecutaneous TCL patients that have received a minimum of one prior sys-temic therapy,389 while three Phase II trials for multiple myeloma andperipheral TCL are still recruiting patients. Romidepsin acts as a histonedeacetylase (HDAC) inhibitor; HDACs catalyze the removal of acetylgroups from acetylated lysine residues in histones, resulting in the modu-lation of gene expression. HDACs also deacetylate non-histone proteins,




such as transcription factors. In vitro, romidepsin causes the accumulationof acetylated histones, and induces cell cycle arrest and apoptosis of somecancer cell lines with IC50 values in the nanomolar range. The mechanismof the antineoplastic effect of romidepsin observed in nonclinical and clin-ical studies has not been fully characterized.383–391 In January 2010,Celgene Pharmaceuticals completed the acquisition of GloucesterPharmaceuticals.392

6.3. Neurological Diseases

6.3.1. Galantamine hydrobromide

Galantamine hydrobromide (42; Reminyl®; Janssen, 2002), is used for thetreatment of mild to moderate Alzheimer’s disease and various othermemory impairments, particularly those of vascular origin.208–210,393–397 Itis an Amaryllidaceae alkaloid obtained from Galanthus nivalis that hasbeen used traditionally in Bulgaria and Turkey for neurological condi-tions.398,399 Galantamine (42) is a competitive, reversible cholinesteraseinhibitor. It reduces the action of acetylcholinesterase (AChE) and there-fore tends to increase the concentration of acetylcholine in the brain. It ishypothesized that this action might relieve some of the symptoms ofAlzheimer’s. It was launched onto the market as a selective acetyl-cholinesterase inhibitor for Alzheimer’s disease treatment, slowing theprocess of neurological degeneration by inhibiting acetylcholinesterase

46 Brahmachari


H

O

O

HN O

HN

O

H

HN

S

SO

NHO

Romidepsin (41)


as well as binding to and modulating the nicotinic acetylcholine recep-tor.54,401,402 Approximately 75% of a dose of galantamine is metabolizedin the liver. In vitro studies have shown that hepatic CYP2D6 andCYP3A4 are involved in galantamine metabolism. Galantamine waslaunched in Austria as Nivalin® in 1996 and as Reminyl® in the rest ofEurope and the US in 2002.72

6.3.2. Apomorphine hydrochloride

Apomorphine hydrochloride (44; Apokyn®; Bertek, 2004), is a semi-synthetic derivative of opium alkaloid morphine (43) isolated frompoppy (Papaver somniferum), and it has long been known for its erectileactivity at the effective dose of 2–6 mg; physicians discovered the effectover 100 years ago, but found the drug, at a much higher dose (ca.200 mg), to be more suitable for poison victims as an emetic because italso causes serious nausea and vomiting.61 Apomorphine exerts its erec-tile effect at the central nervous system; the drug has been found to be anon-selective dopamine agonist which activates both D1-like and D2-like



OOH

MeO

N

Me

Galantamine (42)

HO

H

NCH3

OHO

Morphine (43)

N

HCH3

HO

HO

Apomorphine (44)


receptors, with some preference for the latter subtypes.403–407 This potentdopamine receptor agonist is used to treat Parkinson’s disease, a chronicneurodegenerative disease caused by the loss of pigmented mesostriataldopaminergic neurons linking the substantia nigra (pars compacta) to theneostriatum (caudate nucleus and putamen); subcutaneous apomorphineis currently used for the management of sudden, unexpected and refrac-tory levodopa-induced off states in fluctuating Parkinson’s disease.408–413

Apomorphine has been reported to be an inhibitor of β-amyloid fibril for-mation, and may thus have potential as a therapeutic for Alzheimer’sdisease.414–416

6.3.3. Ziconotide

Ziconotide (45; Prialt™; Elan, 2004), is a non-opioid and non-NSAIDanalgesic agent used for the amelioration of severe and chronic pain. It isa synthetic version of the N-type calcium channel blocker ω-conotoxinMVIIA, a peptide first isolated from the venom of cone snail (Conusmagus) venom.417–420 In December 2004, the Food and DrugAdministration approved ziconotide (45) when delivered as an infusioninto the cerebrospinal fluid using an intrathecal pump system for thetreatment of severe chronic pain, and is currently used in pain manage-ment.421–423 Ziconotide (45), the synthetic form of peptide ω-conotoxin,acts as a selective N-type voltage-gated calcium channel blocker.424–427

This action inhibits the release of pro-nociceptive neurochemicals likeglutamate, calcitonin gene-related peptide (CGRP), and substance P in thebrain and spinal cord, resulting in pain relief.423–426 In 2005, Elanlaunched ziconotide (45) in US and Europe for the treatment of patientssuffering from chronic pain. Rights for marketing ziconotide (Prialt™) inEurope was obtained by Eisai in March 2006.428

48 Brahmachari


H2N-CKGKGAKCSRLMYDCCTGSCRSGKC-CONH2

Ziconotide (45)


6.3.4. Dronabinol and Cannabidol

Dronabinol (46) and cannabidol (47) (Sativex®; GW Pharmaceuticals,2005), as a mixture formulation named as Sativex (tradename), the world’sfirst pharmaceutical prescription medicine derived from the cannabis plant(Cannabis sativa L.).429,430 The drug (a mixture of dronabinol (46) andcannabidol (47)), was launched in Canada in April 2005 for neuropathicpain relief in multiple sclerosis,431–433 and was also approved by HealthCanada in August 2007 as an adjunctive analgesic for severe pain inadvanced cancer patients by reducing the use of breakthrough opioid med-ications. Sativex® has also been found to reduce pain efficiently in patientswith advance cancer,434 and has been recommended by FDA to enterdirectly in Phase III trials. In November 2009, GW Pharmaceuticals dis-closed that recruitment for Phase II/III cancer pain trial of Sativex® hasbeen completed. In March 2010, GW Pharmaceuticals provided an updateon the progress of regulatory submission for Sativex® oromucosal sprayfor the treatment of the symptoms of spasticity due to multiple sclerosis.435



Dronabinol (46)

O

Me

OH

Me

OH

HO

Cannabidol (47)

Mammalian tissues contain at least two types of cannabinoid recep-tors, CB1 and CB2. The active cannabinoid ingredients of Sativex® reactwith the cannabinoid receptors. A receptor on a brain cell can stick or“bind” certain substances for a while. If this happens, it has an effect onthe cell and the nerve impulses it produces, which causes a “dimmingdown” of the symptoms of spasticity. In patients who respond toSativex®, it is this effect that helps to improve their symptoms of spastic-ity and to help them cope better with their usual daily activities. It hasbeen hypothesised that these endogenous cannabinoids function in theCNS as “retrograde synaptic messengers” being released from postsynaptic


neurons and traveling backwards across synapses to activate presynapticCB1 receptors and to suppress neurotransmitter release. The mechanisms,by which the biological actions of endogenous cannabinoids are termi-nated, have not been fully evaluated. However, it appears likely that theyare removed from the extracellular space by tissue uptake and that intra-cellular metabolism via an enzyme system, fatty acid amide hydrolase(FAAH), is also involved.436–438

6.3.5. Lisdexamfetamine

Lisdexamfetamine (48; L-lysine-D-amphetamine, NRP104; Vyvanse®; NewRiver and Shire Pharmaceuticals, 2007), a psychostimulant prodrug (soldunder the tradename Vyvanse®) of the phenethylamine and amphetaminechemical classes, consists of dextroamphetamine coupled with the essentialamino acid L-lysine. Lisdexamfetamine (48) is indicated for the treatment ofattention deficit hyperactivity disorder (ADHD) in children 6–12 years andin adults (April 2008) as an integral part of a total treatment program thatmay include other measures (i.e. psychological, educational, and social).Attention-deficit hyperactivity disorder (ADHD), a neurodevelopmental dis-order in which dopaminergic and noradrenergic neurotransmission aresupposed to be dysregulated, is primarily characterized by the co-existenceof attentional problems and hyperactivity.439–441

50 Brahmachari


NH

NH2

O

NH2

Lisdexamfetamine (48) Amphetamine (49)

NH2

Methylphenidate and amphetamines have been used for ADHD man-agement for many years but due to abuse potentials, these drugs arecontrolled substances.442 Lisdexamfetamine itself is inactive and acts as aprodrug to dextroamphetamine upon cleavage of the lysine portion of themolecule. It was developed for the intention of creating a longer-lasting andmore-difficult-to-abuse version of dextroamphetamine, as the requirement


of conversion into dextroamphetamine in the gastrointestinal tractincreases its duration and renders it ineffective upon any other ingestionroutes than the oral route.443 Intravenously administered lisdexamfeta-mine initially produced effects similar to placebo, and thereforeintravenous abuse is completely ineffective; there is no increased onset oreffect as occurs with intravenous administration of dextroamphetaminecompared to oral use of the same.444 In February 2007, New River andShire Pharmaceuticals obtained FDA approval for use of lisdexamfeta-mine (48) to help ADHD, and in April 2007, Shire bought New River.72

Vyvanse®, the prodrug of dextroamphetamine, is thought to block thereuptake of norepinephrine and dopamine into the presynaptic neuron andincrease the release of such monoamines into the extra-neuronal space.Norepinephrine and dopamine contribute to maintaining alertness,increasing focus, and sustaining thought, effort, and motivation. However,the exact therapeutic action in ADHD is not known.445–448

6.3.6. Methylnaltrexone

Methylnaltrexone (50; Relistor®; Wyeth, 2008), an N-methyl derivative ofnaltrexone (51), contains a charged tetravalent nitrogen atom and remainsunable to cross the blood–brain barrier (BBB), and so has antagonisteffects throughout the body.449,450 Methylnaltrexone (50) binds to thesame receptors as opioid analgesics such as morphine, but it acts as anantagonist, blocking the effects of those analgesics, specifically the con-stipating effects on the gastrointestinal tract.451–455 Furthermore, asmethylnaltrexone cannot cross the blood–brain barrier, it does not reverse



O

O

HO

HON

HMe

+

Br −

Methylnaltrexone (50)

O

O

HO

HON

H

Naltrexone (51)


the pain-killing properties of opioid agonists or cause withdrawal symp-toms. This is the primary difference that makes methylnaltrexone behavedifferently from naltrexone (51), an approved drug used in managementof alcohol and opioid dependence.452–459

Methylnaltrexone (50), thus, blocks peripheral opioid receptors acti-vated by opioids administered for pain relief that cause side effects suchas constipation, urinary retention and severe itching. In May 2007, Wyethand Progenics filed an NDA for subcutaneous doses of methylnaltrexone(50) for the treatment of opioid-induced constipation (OIC) and other painindications. In March 2008, Wyeth and Progenics reported that methylnal-trexone (50) failed in two Phase III trials for intravenous use in thetreatment of post-operative ileus. In April 2008, Progenics and Wyethannounced that Health Canada and the FDA have approved methylnal-trexone (50) for the treatment of OIC. Since May 2009, an oralformulation of methylnaltrexone (50) is under Phase II trials against OICin chronic pain. After acquisition of Wyeth by Pfizer in October 2009,both decided for joint operations.

6.3.7. Capsaicin

Capsaicin (52; Qutenza®, NeurogesX, 2009), an active component of chilipeppers belonging to genus Capsicum, was first isolated in pure and crys-talline form by John Clough Thresh in 1876.460 Capsaicin is currentlyused in topical ointments to relieve the pain of peripheral neuropathy; theburning and painful sensations associated with capsaicin (capsaicin doesnot actually cause a chemical burn, or any direct tissue damage at all) resultfrom its chemical interaction with sensory neurons.461–463 Capsaicin, beinga member of the vanilloid family, binds to the ion channel receptor vanilloid

52 Brahmachari


NH

HO

MeO

O

Capsaicin (52)


receptor subtype 1 (VR 1), thereby permitting cations to pass through thecell membrane and into the cell when activated. The resulting depolariza-tion of the neuron stimulates it to signal the brain.464,465 In November2009, NeurogesX gained FDA approval for Qutenza® (a transdermal 8%patch of capsaicin (52)) against neuropathic pain combined with posther-petic neuralgia. In April 2010, NeurogesX launched Qutenza in US and isplanning to market it in Europe by Astellas Pharma Europe Ltd.466

6.4. Cardiovascular and Metabolic Disease Area

6.4.1. Zotarolimus

Zotarolimus (53; Endeavor™ stent; ABT-578; Medtronic, 2005), a semi-synthetic derivative of sirolimus (34), was designed for use in stents withphosphorylcholine as a carrier; coronary stents reduce early complications



R

OMe

O

N

O

O

OO

OH

MeOO

O

HO

O

MeO

Sirolimus (34): R =

Zotarolimus (53): R = N

NN

N

OH


and improve late clinical outcomes in patients needing interventional car-diology. Sirolimus (34; Rapamune, Wyeth) was originally discovered frombacterium Steptomyces hygroscopicus with promising antifungal activ-ity467,468 and is being used along with other coronary stents againstrestenosis of coronary arteries due to balloon angioplastyis. Zotarolimus(53) is an active principle of Endeavor™ (tradename) stent that inhibitscell proliferation, preventing scar tissue formation and minimizes resteno-sis in angioplasty patients [469]. In July 2005, Medtronic receivedEuropean approval for the sale of the Endeavor drug-eluting coronary stentthat consists of a cobalt-based alloy integrated with a biomimetic phos-phorylcholine polymer.470–472 In February 2008, Medtronic received FDAapproval for the use of Endeavor® against coronary artery disease,473 whileCypher® is being marketed by Cordis (Johnson & Johnson).474

6.4.2. Tiotropium bromide

Tiotropium bromide (54; Spiriva®; Boehringer-Ingelheim/Pfizer, 2004)has been approved by the US Food and Drug Administration (FDA) for thetreatment of bronchospasm associated with chronic obstructive pulmonarydisease (COPD).475 Tiotropium, a derivative of atropine from Atropabelladonna (Solanaceae), is a potent reversible nonselective inhibitor of

54 Brahmachari


N

H

OO

OH

MeMe

O

SS

+

Br−

Tiotropium bromide (54)


muscarinic receptors. Tiotropium is structurally analogous to ipratropium,a commonly prescribed drug for COPD, but this anticholinergic bron-chodilator has shown longer-lasting effects (24 hours). Although the drugdoes not display selectivity for specific muscarinic receptors, on topicalapplication it acts mainly on M3 muscarinic receptors located on smoothmuscle cells and submucosal glands not to produce smooth muscle con-traction and mucus secretion, thus producing a bronchodilatory effect.476

Tiotropium bromide (54) capsules for inhalation are co-promoted byBoehringer-Ingelheim and Pfizer under the trade name Spiriva®.477,478

6.4.3. Bivalirudin

Bivalirudin (55; Angiomax®; The Medicines Company [MDCO], 2000) is aleech antiplatelet protein that is an inhibitor of collagen-induced plateletaggregation.479 Chemically, it is a synthetic congener of the naturally occur-ring drug hirudin (found in the saliva of the medicinal leech Hirudomedicinalis). Bivalirudin (55) is a new, genetically engineered form ofhirudin, the substance in the saliva of the leech (Haementeria officinalis),and stops blood clotting, acting as a specific and reversible direct thrombininhibitor (DTI).479,480 Bivalirudin is used to reduce the risk of blood clottingin adults with severe chest pain (unstable angina) who are undergoing a pro-cedure to open blocked arteries in the heart.481 Bivalirudin overcomes manylimitations seen with indirect thrombin inhibitors, such as heparin;bivalirudin is a short, synthetic peptide that is potent, highly specific, and areversible inhibitor of thrombin.480–483 It inhibits both circulating and clot-bound thrombin,483 while also inhibiting thrombin-mediated plateletactivation and aggregation.484 Bivalirudin has a quick onset of action and ashort half-life,480 and does not bind to plasma proteins (other than thrombin)or to red blood cells, thereby offering a predictable antithrombotic response.

D-Phe-L-Pro-L-Arg-L-Pro-Gly-Gly-Gly-Gly-L-Asn-Gly-L-Asp-L-Phe-L-Glu-L-Glu-L-Ile-L-Pro-L-Glu-L-Glu-L-Tyr-L-Leu

Bivalirudin (55)

Bivalirudin directly inhibits thrombin by specifically binding bothto the catalytic site and to the anion-binding exosite of circulating andclot-bound thrombin. Thrombin is a serine proteinase that plays a central




role in the thrombotic process. It cleaves fibrinogen into fibrin monomers,and activates Factors V, VIII, and XIII, allowing fibrin to develop a cova-lently cross-linked framework which stabilizes the thrombus. Thrombinalso promotes further thrombin generation, and activates platelets, stimu-lating aggregation and granule release. The binding of bivalirudin tothrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in the recovery of thrombin active site functions.480–491

6.4.4. Rosuvastatin calcium

Rosuvastatin calcium (56; Crestor®; AstraZeneca, 2003), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and aderivative of mevastatin isolated from Penicillium citrinum and P. brevicom-pactum, is an effective lipid-lowering agent approved internationally (inmost of Europe, the US, and Canada) for the management of dyslipi-demias.215–217,492,493 Like other available HMG-CoA reductase inhibitors(atrovastatin, fluvastatin, lovastatin, pravastatin, and simvastatin), rosuvas-tatin competitively inhibits the rate-limiting step in the formation ofendogenous cholesterol by HMG-CoA reductase. Consequently, hepaticintracellular stores of cholesterol are reduced, which results in reduced serumlevels of low-density lipoprotein-cholesterol (LDL-C) and triglycerides, andincreased serum levels of high-density lipoprotein-cholesterol (HDL-C), andthus improves the overall lipid profile of patients.494 Pitavastatin (Livalo,

56 Brahmachari


N

HO

OH

COOH

S MeMe

O O

F

Rosuvastatin (56)


Sankyo/Kowa, 2003), an analog of mevastatin-like rosuvastatin, has beenapproved for the treatment of dyslipidemia in Japan.495

6.5. Diabetes

6.5.1. Exenatide

Exenatide (57; Byetta™; Amylin and Eli Lilly, 2005), originally namedexenatide-4, is a 39-amino acid peptide isolated from the oral secretionsof the Gila monster (Heloderma suspectum), a poisonous lizard found inthe southwestern US and northern Mexico, and the first insulin mimeticfound to improve glycemic control.496–498 Subcutaneous exenatide (57)was launched in the US for use in patients with type 2 diabetes who havefailed in glycemic control by treatment with metformin and/or a sulfony-lurea.499,500 Exenatide (57) has a structure similar to glucagon-likepeptide-1 (GLP-1), a human hormone that helps the pancreas to regulateglucose-induced insulin secretion when the blood glucose levels are ele-vated, and is the first compound in a new class of drugs called “incretinmimetics”;501,502 it enhances glucose-dependent insulin secretion by thepancreatic β-cells, suppresses inappropriately elevated glucagon secretion,and slows gastric emptying, although the mechanism of action is stillunder study. Eli Lilly obtained FDA in April 2005 while AmylinPharmaceuticals gained EMEA approval in November 2006 for the use ofa synthetic version of exenatide (57) as an adjunctive therapy in type 2diabetes mellitus.503,504 Amylin Pharmaceuticals, Eli Lilly and Alkermesin May 2009 submitted a NDA for subcutaneous dosing of exenatide (57)once weekly to the FDA, which was accepted in July 2009.

L-His-Gly-L-Glu-Gly-L-Thr-L-Phe-L-Thr-L-Ser-L-Asp-L-Leu-L-Ser-L-Lys-L-Gln-L-Met-L-Glu-L-Glu-L-Glu-L-Ala-L-Val-L-Arg-L-Leu-L-Phe-L-Ile-L-Glu-L-Trp-l-Leu-L-Lys-L-Asn-Gly-Gly-L-Pro-L-Ser-L-Ser-Gly-L-Ala-L-Pro-L-Pro-l-Pro-L-ser-NH2

Exenatide (57)

6.6. Few Other Disease Areas

6.6.1. Pimecrolimus

Pimecrolimus (58; Elidel®; Novartis, 2001) is a novel macrolactum deriv-ative of ascomycin, isolated as a fermentation product of Streptomyces




hygroscopicus var ascomyceticus. Pimecrolimus (58) is an immunomod-ulating agent used in the treatment of atopic dermatitis (eczema). It iscurrently available as a topical cream, once marketed by Novartis (how-ever Galderma Pharmaceuticals is promoting the compound in Canadasince early 2007) under the tradename Elidel®. Its mechanism of actioninvolves blocking T cell activation via the pimecrolimus–macrophilincomplex that prevents the dephosphorylation of the cytoplasmic compo-nent of the nuclear factor of activated T cells (NF-AT). Pimecrolimus alsoprevents the release of inflammatory cytokines and mediators from mastcells. This drug was approved for the treatment of inflammatory skin dis-eases such as allergic contact dermatitis and atopic dermatitis.180,181,505–517

6.6.2. Nitisinone

Nitisinone (59; Orfadin®; Swedish Orphan, 2002) is a derivative of lepto-spermone,518 an important new class of herbicides from the bottlebrush plant(Callistemon citrinus), and exerts an inhibitory effect for p-hydroxyphenyl-pyruvate dioxygenase (HPPD) involved in plastoquinone synthesis; the

58 Brahmachari


O

N

O

O

Cl

MeO

OH

O O

O

OH

OMeOMe

Pimaecrolimus (58)


drug (59) originally developed as an herbicide is now used successfully inthe treatment of hereditary tyrosinemia type 1 (HT-1), a severe inherited dis-ease of humans caused by a deficiency of fumaryl acetoacetate hydrolase(FAH), leading to accumulation of fumaryl and maleyl acetoacetate, andprogressive liver and kidney damage.208–210,519–522 The mechanism of actionof nitrisinone involves reversible inhibition of 4-hydroxyphenylpyruvateoxidase,519,523 thus preventing the formation of maleylacetoacetic acid andfumarylacetoacetic acid, which have the potential to be converted to suc-cinyl acetone, a toxin that damages the liver and kidneys.524

6.6.3. Miglustat

Miglustat (60; Zavesca®; Actelion, 2003) has been approved for patientsunable to receive enzyme replacement therapy as a therapeutic drug fortype 1 Gaucher disease (GD1). Miglustat (OGT 918, N-butyl-1-deoxyno-jirimycin), a semi-synthetic derivative of 1-deoxynojirimycin isolatedfrom the broth filtrate of Streptomyces lavendulae, is an analog of D-glu-cose and a white to off-white crystalline solid that has a bitter taste. Type1 Gaucher disease is an autosomal recessive disorder one gets from bothparents. Gaucher disease is a progressive lysosomal storage disorder asso-ciated with pathological accumulation of glucosylceramide in cells of themonocyte/macrophage lineage. People with type 1 Gaucher have a defectin the enzyme called glucocerebrosidase (also known as glucosylceramidesynthase) that acts on a fatty substance glucocerebroside (also known asglucosylceramide). Accumulation of glucosylceramide causes liver andspleen enlargement, changes in the bone marrow and blood, and bonedisease. Miglustat (60) reversibly inhibits the activity of glucosylceramidesynthase, the ceramide-specific glucosyltransferase that catalyzes the for-mation of glucocerebroside (i.e. glycosphingolipids) and thereby decreases



O

OO

F3C

NO2

Nitisinone (59)


tissue storage of glucosylceramide. Miglustat is, thus, a glucosylceramidesynthase inhibitor.215–217,525–527

Treatment with miglustat (60) is known as substrate reduction therapy(SRT). Unlike enzyme replacement therapy (ERT), which has a direct effecton the breakdown of glycosphingolipids, the concept of SRT in Gaucherdisease involves reduction of the delivery of potential storage material to themacrophage system. Patients treated with miglustat for 3 years show sig-nificant improvements in organ volumes and haematological parameters.Miglustat was effective over time and showed acceptable tolerability inpatients who continued with treatment for 3 years. Miglustat is used to treatadults with mild to moderate type 1 Gaucher disease and it is the first treat-ment to be approved for patients with Niemann-Pick type C disease.Miglustat may only be used in the treatment of type 1 Gaucher patients forwhom enzyme replacement therapy is unsuitable; it has been approved byboth the European Union and FDA for the treatment of progressive neuro-logical manifestations in adult or pediatric patients with Niemann-Pick typeC disease (NPC). It has also been approved for NPC treatment in Canada,Switzerland, Brazil, Australia, Turkey and Israel.528–531

6.6.4. Mycophenolate sodium

Mycophenolate sodium (62; Myfortic®; Norvatis, 2003) is an immunosup-pressant drug used to prevent rejection in organ transplantation. It is aselective, noncompetitive, reversible inhibitor of inosine monophosphatedehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathwayof guanosine nucleotide synthesis. Thus, mycophenolic acid (61), originally

60 Brahmachari


N

CH3

OH

HO

OHHO

N

HO

HO

HO

OH

CH3

(N-Butyl-deoxynojirimycin)

Miglustat (60)


purified from Penicillium brevicompactum, has a selective antiproliferativeeffect on B- and T-lymphocytes that rely on the de novo synthesis ofpurine, and is used for the prophylaxis of organ rejection in patients receiv-ing allogeneic renal transplants treated with cyclosporin (cyclosporin A)and corticosteroids. Mycophenolate sodium is particularly indicated for theprevention of renal transplant rejection in adults; besides, the drug has alsobeen used to prevent rejection in liver, heart, and/or lung transplants inchildren over 2 years. Mycophenolic acid was initially marketed as the pro-drug mycophenolate mofetil (63; MMF) to improve oral bioavailability.More recently, the salt mycophenolate sodium has been introduced.Mycophenolic acid (63) is commonly marketed under the tradenamesCellCept® (63; mycophenolate mofetil; Roche) and Myfortic® (62;mycophenolate sodium; Novartis).215–217,532–560

7. Natural Product-Based Drugs in Clinical Developments

Natural products (NP) or natural product-derived compounds undergoingclinical developments in various disease areas are summarized in thissection. Drug candidates are categorized (Tables 2–5) according the nat-ural sources of their corresponding leads, viz. plant (Table 2 and Fig. 2),microorganism (Table 3 and Fig. 3), marine (Table 4 and Fig. 4) and animal(Table 5 and Fig. 5) sources. Each drug candidate is also supplemented withits structure, code name, disease indication, mechanism of action, develop-ment status and name of the developer including respective references.



OH

Me

MeO

O

O

HO

O

OH

Me

MeO

O

O

NaO

O

Mycophenolic acid (61)

Mycophenolate sodium (62)

OH

Me

MeO

O

O

O

ON

O

Mycophenolate mofetil (63)


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Table 2. Plant-derived natural product-based drug candidates under clinical evaluation.

Lead compound Disease area/ Development(Str. No.) Compound class Name (synonym) Indication Mechanism of action status Developer References

Artemisinin (8) Endoperoxide Arterolane Antiparasitic Under study (on Phase III Ranbaxy 561–565sesquiterpene (RBX11160, (antimalarial) interation of peroxidelactone OZ-277) (64) moiety with parasite

targets)

Betunilic acid (65) Triterpenoid Bevirimat (PA-457) Antiviral (anti- Inhibits the final step of Phase IIb Panacos 566–573(66) HIV) the HIV Gag protein Pharmaceuticals

processing and thusblocks HIV maturation

Betunilic acid (ALS- Oncology Inhibits transcription Phase I Advanced Life 574–576357) (65) factor specificity Sciences (UIC)

protein-1 (Sp1), Sp3,and Sp4 activation

Castanospermine (67) Indolizine alkaloid MX-3253 (formerly Antiviral Inhibits α-glucosidase I Phase II MIGENIX 577–581MBI-3253; [Hepatitis C (received licenseCelgosivir; 6-O- virus (HCV)] from Virogenbutanoyl Ltd., UK)castanospermine)(68)

4-Methylumbelliferone Coumarin Heparvit® (dietary Antiviral (anti- Promotes bile discharge, Phase II MTmedical Institute 582(Hymecromone) (69) supplement) HBV and and inhibits hyaluronan of Health and

anti-HCV) biosynthesis BioMonde

1,5-Di-caffeoylquinic Cyclic polyolic 1,5-DCQA (70) Antiviral (Anti- Inhibits HIV-1 integrase Phase I/II Chinese Academy 583–585acid (70) derivative HIV HIV/AIDS of Military

and hepatitis B) Medical Sciences

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Huperzine-A (71) Sesquiterpene Huperzine-A (71) Neurological Acetylcholinesterase Clinical Chinese scientists 586–591alkaloid (Alzheimer’s (AChE) inhibitor development

Disease) Phase II NIA, a division ofNIH

Morphine (43) Alkaloid Morphine-6- Neurological Mediates its effects by Phase III CeNeS 592, 593glucuronide (pain; activating the micro- Pharmaceuticals/(M6G) (72) analgesic) opioid receptor; it PAION

shows equivalent Pharmaceuticalsanalgesia to morphinebut to have a superiorside-effect profile interms of reducedliability to inducenausea and vomitingand respiratorydepression.

Lobeline (73) Piperidine Lobeline (73) Neurological Reduces the Phase II Yaupon 594–599alkaloid (treatment of methamphetamine Therapeutics

methamphet- induced dopamine and NIHamine releaseaddiction andADHD)

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Capsaicin (52) Capsaicinoid Capsaicin (Coded Neurological Binds to vanilloid Phase III Anesiva 461, 6004975; ALGRX (pain receptor subtype 14975;AdleaTM) indications (VR1)(52) such as severe

Civanex® post-surgical(zucapsaicin pain,cream 0.075%; posttraumaticWL-1001) neuropathic

pain andmusculoskeletaldiseases)

Osteoarthritis -do- Phase III Winston 601pain Laboratories, Inc.

Phlorizin (74) Polyphenolic Dapagliflozin Antidiabetic Sodium glucose Phase III Bristol-Myers 602–607glycoside (BMS-512148) co-transporters Squibb (BMS)

(75) (SGLTs) inhibitor thatlowers glucose plasmalevel and improvesinsulin resistance.

Resveratrol (76) Triphenolic SRT-501 Against diabetes Activates sirtuins.by Phase II Sirtris 608–614stilbene (a formulation) and obesity working indirectly, via Pharmaceuticals

the energy sensorAMP-activated proteinkinase (AMPK)

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Ajulemic acid (77) Cannabinoid CP 7075 (IP 751, Neurological Suppresses IL-1β and Phase I Cervelo 615–618ajulemic acid, (neuropathic matrix PharmaceuticalsCT-3) (synthetic pain) metalloproteinasesversion) (MMPs) through a

peroxisomeproliferator-activatedreceptor (PPAR)γ-mediated mechanism

1-Deoxynojirimycin Aza-sugar-type Isofagomine Gaucher’s Mimics the carbocation Phase II Amicus 619–622(Moranoline; 78) (PliceraTM, disease, a transition state used by Therapeutics in

AT2101) (79) lysosomal glycosidases collaborationstorage with Shiredisorder Pharmaceuticalscaused by β-glucocerebro-sidasedeficiency

Himbacine (80) Alkaloid SCH 530348 Cardiovascular Thrombin receptor Phase III Schering-Plough 623–626(TRA) (81) diseases antagonist (acute

(antiplatelet coronaryagent) syndromes)

Eupatilin (82) Flavone DA-6034 (83) Dry eye systems Suppresses MMP-9 and Phase I Dong-A 627–629inflammatory cytokines Pharmaceuticalsand activates MAPKSignaling pathway

(Continued )


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Gastritis Stimulates endogenous Phase IIprostaglandin E2

(PGE2) synthesis aswell as mucussecretion

Camptothecin (84) Quinoline alkaloid Karenitecin® Oncology Inhibits topoisomerase I Phase III BioNumerik and 149,(BNP-1350) (85) (ovarian ASKA 630–634

cancer) PharmaceuticalDiflomotecan Oncology (advance Inhibits topoisomerase I Phase II Ipsen 635, 636

(BN-80915) (86) metastaticcancers)

Gimatecan Oncology (solid Inhibits topoisomerase I Phase II Novartis/Sigma-Tau 637–639(ST-1481) (87) tumor)

Elomotecan Oncology Inhibits topoisomerase I Phase I Ipsen 640(BN-80927, (advancedLBQ707, metastaticR-1559) (88) cancers)

DRF 1042 (89) Oncology Inhibits topoisomerase I Phase II/III Dr Reddy/ClinTec 641, 642International

SN2310 141 (90) Oncology Inhibits topoisomerase I Phase I 643

Combretastatin A-4 Stilbenoid phenol Combretastatin A-4 Oncology Tubulin binding Phase I/II/III OXiGENE 644–650(91) phosphate (vascular (Arizona State)

(ZybrestatTM, disruptingCA4P) (92) agent)

Ombrabulin Oncology Tubulin binding Phase III Sanofi-Aventis 644, 645,(AVE-8062; 651AC-7700) (93)

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Combretastatin A-1 Stilbenoid phenol OXi4503 Oncology Tubulin binding Phase I/II OXiGENE 652–657(94) (Combretastatin (advanced- (Arizona State)

A-1 diphosphate) stage solid(95) tumors)

Paclitaxel (96) Diterpene taxoid Cabazitaxel Oncology Tubulin binding Phase III Sanofi-Aventis 658–662(XRP-6258) (97) (pancreatic and

hormone-refractoryprostatecancers)

Larotaxel Oncology Tubulin binding Phase III Sanofi-Aventis 658, 659,(XRP-9881) (98) (pancreatic and 661–664

hormone-refractoryprostatecancers)

DHA-paclitaxel Oncology Tubulin binding Phase III Luitpold 665, 666(Taxoprexin®) (metastatic Pharmaceuticals(99) melanoma)

Ortataxel Oncology (solid Tubulin binding Phase I/II Spectrum (Indena) 667–669(IDN-5109, tumors)BAY-59-8862)(100)

Milataxel Oncology Tubulin binding Phase II Wyeth 670, 671(MAC-321, (colorectal PharmaceuticalsTL-00139) (101) neoplasm)

(Continued )


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Tesetaxel (DJ-927) Oncology Tubulin binding Phase I/II Daiichi Sankyo/ 673–677(102) (advanced Genta

gastric andbreast cancer)

TPI-287 (103) Oncology Tubulin binding Phase II Tapestry 678(advanced Pharmaceuticalspancreaticcancer)

BMS-188797 (104) Oncology Tubulin binding Phase II Bristol-Myers 679–681(advanced Squibb (BMS)malignancies)

Vinblastine (105) Vinca alkaloid Vinflunine (Javlor®) Oncology Tubulin binding Phase III Pierre Fabre 682–687(106) (bladder Laboratories

cancer)

Noscapine (107) Benzyl- CB3304 Oncology Tubulin binding Phase I/II Cougar 682–684,isoquinoline (Noscapine) (multiple Biotechnology 688, 689alkaloid (107) myeloma)

Curcumin (108) Polyphenol Curcumin (108) Inflammation; Various anti- Phase I/II Being conducted by 690–692oncology inflammatory and Phase II various concerns(matastatic antioxidative (MCC) worldwidecolon cancer) properties

Oleanolic acid (109) Triterpenoid RTA-402 Oncology Inhibits IκB alpha kinase Phase I/II Reata 693, 694(CDDO-Me) (prostate activation Pharmaceuticals(110) cancer)

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Chronic kidney Regulates transcription Phase II Reata 695disease (CKD) factor Nrf2 Pharmaceuticalsin type 2diabetesmellituspatients

β-Lapachone (111) Naphthaquinone β-Lapachone Oncology Increases pro-apoptic Phase II ArQule 696–699(ARQ-501) (111) (pancreatic and protein E2F1, as well

ovarian cancer) as induces expressionof cyclin dependentkinase inhibitor 1A(CDKN1A or P21)

Rohitukine (112) Flavone Alvocidib Oncology Cyclin-dependent kinase Phase III Sanofi-Aventis 700–702(flavopiridol, inhibition (NSCLC)HMR 1275) Phase IIb(113) (CLL)

Daidzein (114) Isoflavone Phenoxodiol (115) Oncology NADH oxidase (tNOX) Phase III Marshall Edwards 703–707and sphingosine-1- (ovarian (Novogen)phosphate inhibition cancer)

Phase II(castrate andnon-castrateprostatecancer)

Genistein (116) Isoflavone Genistein (116) Oncology Protein-tyrosine kinase Phase I/II Astellas, Bausch & 708(antitumor) inhibition, Lomb

antioxidative

(Continued )


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Flavone-8-acetic acid Flavone derivative ASA404 (DMXAA, Oncology Vascular targeting and Phase III Antisoma 709–713(117) ASA1404) (118) angiogenesis inhibition (University of

Auckland)/Novartis

Silybin (119) Flavonolignoid IdB 1016 (Silipide; Oncology Antioxidant and Phase II American College 714–719Silybin and anti-inflammatory (cancer of Gastro-phosphatidyl- chemo- enterology/choline complex; prevention) IndenaSilophos®)

3′-O-Methyl Lignoid Terameprocol Oncology (solid Transcription inhibitor Phase I/II Erimos (John 720–726nordihydroguaiaretic (EM-1421, tetra- tumors, glioma Hopkins)acid (NDGA; 120) O-methyl and leukemia)

nordihydroguai-aretic acid) (121)

Epipodophyllotoxin Alkaloid Tafluposide (123) Oncology Topoisomerase I and II Phase I Pierre Fabre 727–729(122) inhibitor

Ingenol (124) Tetracyclic Ingenol 3-angelate Oncology Protein kinase C Phase II Peplin 730–733diterpene (PEP005) (125)/ activation

Ingenol mebutate

Acronycine (126) Alkaloid S23906-1 (127) Oncology (solid DNA binding Phase I Laboratoires Servier 734–737tumors) (CNRS)

Homoharringtonine Alkaloid Homoharringtonine Oncology Protein synthesis Phase II/III ChemGenex 738, 739(128) (Omacetaxine inhibition

mepesuccinate;Ceflatonin®)(128)


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Table 3. Microorganism-derived natural product-based drug candidates under clinical evaluation.

Lead compound Compound Disease area/ Development(Str. No.) class Name (synonym) Indication Mechanism of action status Developer References

Cephalosporins β-Lactum Ceftobiprole Antibacterial Inhibits bacterial cell Phase III Basilea 740–744antibiotics medocaril wall synthesis (cSSSIs) Pharmaceutica

(BAL-5788) and J&J affiliated(129) Cilag GmbH

InternationalCeftaroline acetate Antibacterial -do- Phase II Forest 745–748

(PPI-0903, (cSSSIs; LaboratoriesTAK-599) (130) CAP)

Carbapenems β-Lactum Tebipenem pivoxil Antibacterial -do- Phase III Meiji Seika 749–751antibiotics (ME-1211, (otolaryngological/

L-084) (131) respiratoryinfections)

Tomopenem Antibacterial -do- Phase II Daiichi Sankyo 752–754(CS-023, (commonRO4908463, nosocomialR1558) (132) infections)

PZ601 (SM- Antibacterial -do- Phase II Protez, licensed 755, 756216601) (133) from Dainippon

SumitomoME-1036 (CP5609) Antibacterial -do- Phase I Forest and Meiji 757,758

(134) SeikaSulopenem (CP- Antibacterial -do- Phase I Pfizer 759–761

70429) (135)Faropenem daloxate Antibacterial -do- Phase III Replidyne 762–764

(SUN-208, BAY-56-6824) (136)

(Continued )


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Teicoplanin Lipoglyco- Dalbavancin Antibacterial Inhibits bacterial cell Phase III Pfizer 765–769analog peptide (Zeven®, (cSSSIs) wall biosynthesisA40926 (137) antibiotic BI-397) (138) via formation of a

complex with theC-terminal D-alanyl-D-alanineof growingpeptidoglycanchains; in addition,it appears to havethe unique abilityto dimerise andanchor its lipophilicside chain in thebacterial membranes.

Chloroeremomycin Glycopeptide Oritavancin Antibacterial (cSSSIs Inhibits bacterial cell Phase III Eli Lilly/Targanta 770(139) antibiotic (NuvocidTM, LY- including MRSA) wall biosynthesis

333328) (140)

Vancomycin; Glycopeptide TD-1792 (a Antibacterial (cSSSIs Inhibits bacterial cell Phase II Theravance 771Cephalosporin and β- Vancomycin- including MRSA) wall synthesis

lactum Cephalosporinantibiotics heterodimer)

(141)

(Continued )


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Ramoplanin (142) Lipopeptide Ramoplanin factor Antibacterial Inhibits bacterial cell Phase II Oscient 772–777antibiotic A2 (Ramoplanin) [Clostridium wall synthesis Pharmaceuticals

(142) difficile associateddiarrhoea (CDAD)]

Semi-synthetic Macrolide NXL-103 Antibacterial (CAP Inhibits bacterial Phase II Sanofi-Aventis 778–783Streptogramins peptide (XRP2868) — and cSSSIs protein synthesis

antibiotcs a 70:30 mixture including MRSA)of Flopristin(RPR132552A,StreptograminA-type) (143)and Linopristin(RPR202698,StreptograminB-type) (144)

Friulimicin B (145) Lipopeptide Friulimicin B (145) Antibacterial Through complex Phase I MerLion 224,antibiotic formation with Pharmaceuticals 784–786

bactoprenol-phosphate, leadingto the interruptionof peptidoglycanand teichoic acidbiosynthesis.

(Continued )


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Duramycin (146) Polycyclic Moli1901 Antibacterial (cystic Increases chloride Phase II AOP Orphan in 787–789peptide (duramycin, fibrosis) permeability in the collaboration with

2262U90) (146) nasal epithelium Lantibioof healthyindividuals andsubjects withcystic fibrosis

Erythromycin Macrolide Cethromycin Antibacterial (CAP, Inhibits bacterial Phase III Advanced Life 790–795(147) antibiotic (RestanzaTM other respiratory protein synthesis Sciences

(ABT-773) (148) tract infections, by interactingand anthrax) close to the

peptidyltransferase site of the 50Sribosomal subunit.The main bindingsites are withindomains II and Vof the 23S rRNA.

EP-420 Antibacterial (CAP) -do- Phase II Enanta Pharma- 796–798(EP-013420) ceuticals and(149) Shionogi & Co.

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BAL-19403 (150) Antibacterial (acne) Shows strong Pre-clinical/ Basilea 799–801suppression of the Phase I Pharmaceutica AGinflammatoryresponse of humanneutrophils, thewhite blood cellscontributing to theinflammatoryaspects of thedisease.

Telithromycin Antibacterial Inhibits bacterial Phase II/III Sanofi-Aventis 802(Ketek®) (151) (respiratory protein synthesis

infections) by blocking theprogression of thegrowingpolypeptide chainthrough bindingwith the 50Ssubunit of ribosome

Tiacumicin B (152) Macrolactone Tiacumicin B Antibacterial Inhibits bacterial Phase III Optimer 803–809(OPT-80, PAR- [Clostridium RNA synthesis Pharmaceuticals101; identical to difficile-associatedLipiarmycin diarrhea (CDAD)]A3184 andClostomicin B1)(152)

(Continued )


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Aminomethyl- Amino- MK-2764 (PTK- Antibacterial (broad Inhibits bacterial Phase III Paratek/Novartis 810cyclines methyl- 0796; BAY spectrum antibiotic protein synthesis (treatment of

cycline 73-7388) (153) against MRSA, hospitalMDR infections inStreptococcus both oral andpneumoniae and i.v. injectablevancomycin- formulations)resistantenterococci)

Rs-DPLA (154) Lipid-A Eritoran (E5564) Antibacterial (acts Inhibits endotoxin Phase III Eisai 811–818analog (155) against sepsis by response through

Gram-negative antagonism of thebacteria) Toll-like receptor 4

(TLR4)

Rifamycin- Antibiotics CBR-2092 (156) Antibacterial Exerts antimicrobial Phase IIa Cumbre 819, 820quinolone activity through (treatment of Pharmaceuticalsheterodimer combined effects infections

on RNA caused bypolymerase, DNA Gram-positivetopoisomerase IV cocci)and DNA gyrase

(Continued )


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WAP-8294A2 Antibiotic WAP-8294A2 (157) Antibacterial (MRSA Interacts selectively Various aRigen 821–824(JA-002) (157) infections and to membrane Phase I/II Pharmaceuticals

acne) phospholipids, trials (gel,causing sever cream,damage to injectablebacterial form)membrane

Deoxymulundo- Echinocandin- Aminocandin Antifungal (Candida Targets the glucan in Phase I Novexel 825–827candin (158) type (NXL-201, sp. infections) fungal cell walls

antifungal IP960, HMR-antibiotic 3270) (159)

Patrician A (160) Polyene SPK-843 (161) Antifungal (systemic Destabilizes fungal Phase II Kaken 828–834antibiotic mycosis) cell membrane Pharmaceuticals

Cyclosporin (162) Cyclic NIM 811 (SDZ Antiviral (anti-HCV) Inhibits mitochondrial Phase I Sandoz (now 835–840peptide NIM 811, permeability Novartis)

Cyclosporin 29, transitionMeIle4-cyclosporin)(163)

(Continued )


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Spicamycin Antibiotic KRN5500 (164) Neurology Inhibits protein Phase IIa DARA 841–844(neuropathic pain synthesis by Therapeutics, Inc.in cancer patients, interfering within particular, endoplasmicchemotherapy- reticulum andinduced peripheral Golgi apparatusneuropathy) functions; it also

induces celldifferentiation andcaspase-dependentapoptosis

Galactonojirimycin Aza-sugar Migalastat Fabry disease Stabilizes protein Phase III Amicus 845, 846(Galactostatin) type (AmigalTM, structures and Therapeutics in(165) AT1001, 1- restores correct collaboration with

Deoxygalacto- folding through Shirenojirimycin, 1- binding with them PharmaceuticalsDeoxygalacto-statin) (166)

Staurosporine (167) Bis-indole Ruboxistaurin Diabetes (diabetic Protein kinase C Phase III Eli Lilly 847–853alkaloid (LY333531) peripheral (PKC) inhibitorantibiotic (168) retinopathy)

Cyclosporine-A Macrocyclic Voclosporin (ISA- Immunosuppressive Calcineurin inhibitor Phase IIb Lux Biosciences 854–856(162) peptide 247, R1524) (prevention of

antibiotic (169) the rejectionof kidneygraft)

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Pladienolide D Macrolide E7107 (171) Oncology Binds with Phase I Eisai 857–860(170) antibiotic spliceosome-

associated protein130 (SAP130) andinhibits thesplicing of pre-mRNA resultingcell cycle arrest

Elsamicin A (172) Antibiotic Elsamicin A Oncology Inhibits Phase II Spectrum 861(Elsamitrucin) topoisomerase I Pharmaceuticals(172) and II

Doxorubicin (173) Antibiotic L-Annamycin (174) Oncology Inhibits Phase I/IIa Callisto (M.D. 862topoisomerase II Anderson Cancer

Center)Berubicin (RTA744, Oncology Inhibits Phase II Reata 863, 864

WP744) (175) topoisomerase II PharmaceuticalsSabarubicin (MEN- Oncology Inhibits Phase II (small- Menarini 865–867

10755) (176) topoisomerase II cell lung Pharmaceuticalscancer;SCLC)

Nemorubicin Oncology Inhibits Phase I/II Nerviano Medical 868, 869(MMDX, PNU- topoisomerase II Sciences152243A) (177)

(Continued )


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Distamycin A (178) Antibiotic Brostallicin (PNU- Oncology DNA minor groove Phase II Cell Therapeutics 870–877166196) (179) binder (monotherapy (Nerviano

against STS Medical Sciences)of metastaticor advancedstage)

Geldanamycin (180) Benzoquinone Tanespimycin (17- Oncology Inhibits HSP90 and Phase II/III Kosan (NIH) 878–882ansamycin AAG, KOS-953, interrupts MAPK (anti-antibiotic NSC-330507) pathway melanoma)

(181)Alvespimycin (17- Oncology HSP90 inhibitor Phase I (solid Kosan (NIH) 88, 884

DMAG, KOS- tumors)1022, NSC- Phase II707545) (182) (monotherapy

againstHER2-positivemetastaticbreast cancer)

Retaspimycin (IPI- Oncology HSP90 inhibition Phase I/II Infinity 885, 886504, 17-AAG (breast Pharmaceuticalshydroquinone cancer)salt) (183)

(Continued )


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Sirolimus (34) Macrolide Deforolimus Oncology mTOR inhibition Phase I/II/III Merck and ARIAD 887–890antibiotic (Ridaforolimus; (various

MK-8669, AP- tumor types23573) (184) including

metastaticSTS and bonesarcomas)

Salinosporamide A Antibiotic Salinosporamide A Oncology Proteasome Phase Ib (solid Nereus 891–893(185) (NPI-0052) (185) inhibition tumor

malignancies)

Staurosporine (167) Bis-indole Enzastaurin Oncology Serine–threonine Phase II Eli Lilly 894–898alkaloid (LY317615) (186) kinase inhibition (NSCLC)antibiotic Phase III

(DLBCL;diffuse largeB-celllymphoma)

Midostaurin (PKC- Oncology Inhibits protein Phase I/II Novartis 899412, CGP 41251, kinases including4′-N-Benzoyl- FLT3 inhibitionstaurosporine)(187)

K252a Alkaloidal Lestaurtinib (CEP- Oncology Inhibition of FLT3 Phase II/III Cephalon 900, 901(Staurosporine antibiotic 701, KT-5555) and tyrosineanalog) (188) (189) phosphorylation

of TrkA

(Continued )


82B

rahmachari

b1214B




UCN-01 201 Alkaloidal KRX-0601 (UCN- Oncology Inhibition of CDKs Phase II Keryx (Kyowa 902–905(staurosporine antibiotic 01, KW-2401) (melanoma, Hakko/NCI)analog) (190) (190) TCL, SCLC)

Diazepinomicin Dibenzo- Diazepinomicin Oncology RAS-mitogen- Phase I/II Thallion (Ecopia) 906–910(ECO-4601) diazepine (ECO-4601) activated(191) alkaloid (191) phosphokinase

(MAPK) pathwayinhibitor andinhibition of theperipheralbenzodiazepinereceptor

Prodigiosin Tri-pyrrole Obatoclax (GX15- Oncology Bcl-2 inhibition Phase I/II Gemin X 911, 912(Streptorubin B) antibiotic 070) (193)(192)

Epothilone B (38) Polyketide Patupilone Oncology Microtubulin Phase III Novartis 913, 914macrol- (Epothilone B, stabilization (ovarianactone EPO-906) (38) cancer)(with a Sagopilone (ZK- Oncology Microtubulin Phase II (lung, Schering AG 368,methyl- EPO, ZK- stabilization ovarian and 915–918thiazole 219477) (194) prostategroup) cancers)antibiotic

(Continued )


Natural P

roducts in Drug D

iscovery83

b1214B




Epothilone D (195) -do- 9,10-Didehydro- Oncology Tubulin stabilization Phase I/II Kosan (Memorial 919epothilone D Sloan-Kettering)(KOS-1584)(196)

NPI-2350 Diketo- NPI-2358 (198) Oncology Tubulin binding Phase II Nereus 920–922(halimide, piperazine (NSCLC)phenylahistin)(197)

Illudin S (199) Sesquiter- Irofulven (MGI- Oncology DNA synthesis Phase II/III Eisai (MGI Pharma) 923–926penoid 114, HMAF) inhibition (advanced-

(200) stage PC andadvanced GIsolid tumors)


84B

rahmachari

b1214B


Table 4. Marine-derived natural product-based drug candidates under clinical evaluation.


Anabaseine (201) Tetrahydro- 3-(2,4-Dimethoxy Neurology Enhances cognition; it Phase I/II CoMentis 927–933pyridinyl benzylidene)- (Alzheimer’s acts as a partialpyridine anabaseine disease) agonist at neuralderivative (DMXBA; GTS- nicotinic(a nicotinic 21) (202) acetylcholinecompound) receptors. It binds

to both the α4β2and α7 subtypes,but activatesonly the α7 to asignificant extent

Plitidepsin (Aplidin) Cyclic Plitidepsin (Aplidin®) Oncology Inhibitor to VEGF, Phase II PharmaMar 934–936(203) depsipeptide (203) VEGFR1, and G1/

G2 phase cell cycle

Halichondrin B Macrocyclic Eribulin (E7389, Oncology Tubulin assembly Phase II/III Eisai 937–943(204) polyether NSC-707389) inhibition (advanced or

(205) metastaticbreast cancer)

Hemiasterlin (206) Oligopeptide E7974 (207) Oncology Tubulin assembly Phase I (against Eisai 944inhibition a variety of

human tumorxenografts)

(Continued )


Natural P

roducts in Drug D

iscovery85

b1214B




Psammaplin A (208) Symmetrical Panobinostat (LBH- Oncology Inhibits histone Phase I/II/III Novartis 945,946bromotyrosine- 589) (209) deacetylasederived (HDAC)disulfide

Bryostatin 1 (210) Macrolide Bryostatin 1 (210) Oncology Protein kinase C Phase I/II NCI 947–949lactone inhibition

Jorumycin (211) Dimeric Zalypsis® Oncology DNA binding and Phase I (solid PharmaMar 950, 951isoquinoline (PM00104/50) transcriptional tumors oralkaloid (212) activity lymphoma)

Dolastatin 15 (213) Depsipeptide Tasidotin Oncology Induces G2/M phase Phase II Genzyme 952–954(Synthadotin, cell cycle arrest byILX-651) (214) inhibiting tubulin

assembly

Dolastatin 10 (215) Depsipeptide Soblidotin (YHI-501, Oncology Tubulin assembly Phase II Yakult Honsha 955TZT-1027, inhibition (ASKAAuristatin PE) Pharmaceutical)(216)

Kahalalide F (217) Depsipeptide Kahalalide F (217) Oncology Alters lysosomal Phase II PharmaMar 956–961membrane function

PM02734 (Irvalec®; Oncology Alters lysosomal Phase I PharmaMar 962–965218) membrane function


86B

rahmachari

b1214B


Table 5. Animal-derived natural product-based drug candidates under clinical evaluation

Lead compound Compound Name Disease area/ Development(Str. No.) class (synonym) Indication Mechanism of action status Developer References

Tetrodotoxin Quinazoline Tetrodotoxin Neurology Blocks the action Phase III Wex 139,(TTX; isolated heterocycle (TectinTM/ (Pain) potentials in nerves (TectinTM Pharmaceuticals 966–969from Pufferfish) TetrodinTM) through binding to against (in conjunction(219) (219) sodium channels in neuropathic with Chinese

cell membrane pain in cancer Medicalchemotherapy) Institutes)

Phase I(TetrodinTM inthe managementof opiatewithdrawalsymptoms)

Xen-2174 (220) 13-Amino-acid Xen-2174 (220) Neurology Inhibits norepinephrine Phase II (against Xenome 970–973(isolated from peptide (Pain) transporter (NET) acute post-the snail Conus (a conotoxin) operative painmarmoreus) and chronic

pain in cancerpatient)

Trodusquemine Sulfated Trodusquemine Diabetes Suppresses mammalian Phase I (against Genaera 974–978(221) (isolated aminosterol (MSI-1436) appetite through type 2 diabetes Corporationfrom the liver (221) inhibition of protein and relatedof the dogfish tyrosine phosphatase symptoms)shark, Squalus 1B (PTP-1B)acanthias)

(Continued )


Natural P

roducts in Drug D

iscovery87

b1214B



Lead compound Compound Name Disease area/ Development(Str. No.) class (synonym) Indication Mechanism of action status Developer References

Indolicidin (222) Peptide Omiganan (223) Antibacterial Through bacterial Phase III Developed by MIGENIX; 979–983(isolated from cytoplasmic licensed to Cadenceneutrophils of membrane Pharmaceuticals andbovine) interaction Cutanea Life Sciences

for catheter-relatedinfections (codedOmigardTM, CPI-226,MBI-226) anddermatological diseases(coded as CLS001,MX-594AN),respectively. Primaryend point was notachieved in a Phase IIItrial and additionalPhase III trials using agel-based formulation byCadence Pharmaceuticalsare underway. CutaneaLife Sciences havesuccessfully evaluated222 in Phase II trials(2007) and the Phase IIItrials for treatment ofrosacea, a chronicinflammatory skindisorder are underway.


88 Brahmachari


OO

ONH

O

NH2

Arterolane (64)

H

H

H

HRO

COOH

Betunilic acid (65): R = H

Bevirimat (66): R =

O

COOH

N

OH HOH

OR

OH

Castanospermine (67): R = H

MBI-3253 (Celgosivir) (68): R =

O

O

CH3

OOH

Hymecromone (69)

O

O

HO

HO

HO

HOO

O

OH

OH

HOOC

1,5-DCQA (70)

NH2

N

O

H

Huperzine-A (71)

O

HO

RO

N

HH

Me

Morphine (43): R = H

M6G (72): R = O

HO

HO

OH

HOOC

O

N

OH

Me

Lobeline (73)

OHO

OH

HO O

HOOH

OH

O

OHPhlorizin (74)

Fig. 2. Plant-derived drug candidates under clinical evaluation.




O

Cl

OOH

OH

OH

OH

Dapagliflozin (75)OH

OH

OH

Resveratrol (76)

O

OH

COOH

Ajulemic acid (77)

NH

OH OH

OH

OHNH

OH

OH

OH

1-Deoxynojirimycin (78) Isofagomine (79)

O

O

N

H

H

H

H

Me

Me

Me

O

O

N

H

H

H

H

Me

NH

O

O

F

Himbacine (80)

SCH 53048 (81)

O

OH

OH

O

OMe

OMe

MeO

Eupatilin (82)

OO

O

OMe

OMe

OMe

O

OH

DA-6034 (83)

Fig. 2. (Continued )


90 Brahmachari


N

N

R

O

O

OCH3 OH

Camptothecin (84): R = H

Karenitecin (85): R =

Gimatecan (87): R =

Si

NO

N

N

OF

FO

OOHCH3

Diflomotecan (86)

N

N

N

OCH3

FO

OOHCH3

CH3

Elomotecan (88)

N

N

O

O

OCH3 OH

O

OH

DRF 1042 (89)

N

N

O

O

OCH3 OH

CH3

CH3

CH3

O

O

O

O CH3

SN2310 (90)

(90)





R

OMe

OMe

MeO

OMe

Combretastatin A-4 (91): R = OH

Combretastatin A-4 phosphate (92): R = OPO3Na2

Ombrabulin (AVE-8062) (93): R = NH O

OH

NH2

OR

OMe

OMe

MeO

OMe

OR

Combretastatin A-1 (94): R = HOXi4503 (95): R = PO3Na2

OOOH

O

O

O

H

OO

OH

O

O

ONH

O

R1

OR2

Paclitaxel (96): R1= CH3, R2 = H

BMS-188797 (104): R1 = OCH3, R2 = H

DHA-paclitaxel (99): R1 = CH3, R2 =

O

O

OO

H

OO

OH

O

O

ONH

OH

O

O MeOOMe

Cabazitaxel (97)

OO

O

O

O

H

OO

OH

O

O

ONH

OH

O

O

Larotaxel (98)

O

O

OO

H

OO

OH

O

O

ONH

OH

O

O OHO

O

Milataxel (101)



92 Brahmachari


N

OO

H

OO

OH

O

O

ONH

OH

O

OO

O

F

OO

N

Tesetaxel (102)

TPI-287 (103)

OO

O

O

O

H

OOOH

O

O

ONH

OH

O

O O

N

NH

OH

NCH3O

N

CH3

OH

OAc

H

H3CO2C

HCO2CH3

Vinblastine (105)

N

NH

H

NCH3O

N

CH3

OH

OAc

H

H3CO2C

HCO2CH3

FF

Vinflunine (106)

O

O

ON

CH3

H

O

OMe

OMeMeO

Noscapine (107)

O

OH OH

O

MeO OMe

Curcumin (108)

OO

O

O

O

H

OOO

O

O

ONH

OH

O

OOH

O

O

Ortataxel (100)





H

H

H

OH

COOH

Oleanolic acid (109)

H

HO

CO2CH3

HO

N

RTA-402 (110)

O

O

O

β-Lapachone (111)

N

O

OOH

OH CH3

OH

CH3

Rohitukine (112)

N

O

OOH

OH

OH

CH3

Cl

Alvocidib (113)

O

OR

OH

OH

Daidzein (114): R = HGenistein (116): R = OH Phenoxodiol (115)

O

O

OH

OH

O

O

HOOC

Flavone-8-acetic acid (117)

O

O

HOOC

CH3

CH3

ASA-404 (118)

O

OH

OH

O

OH

O

OOH

OH

OMe

Silybin (119)



94 Brahmachari


OR OR

ORMeO

NDGA (120): R = HTerameprocol (121): R = CH3

O

O

OH

O

H O

OMe

OMe

MeO

Epipodophyllotoxin (122)

O

FF

F

F F

O

O

O

O

O

O

O

O

H O

OMe

O

MeO

POH

OHO

O

O F

F

F

F

FO

Tafluposide (123)

O

RO OHOH

Ingenol (124): R = H

Ingenol mebutate (125): R =

O

N O

O

Me

OMe

Acronycine (126)

N O

O

Me

OMe

OAc

AcO

S23906-1 (127)

O

N

O

O

H

O

OMeO

OMe

OH

OH

Homoharringtonine (128)





S N

N NH

N

S

N

OH O

O

N

O

O

OO

CH3

O

NOH

O

O

HNH2

Ceftobiprole medocaril (129)

S N

N NH

N

S

S

N

OH O

S

NO

O

O

HNH

P

OH

OOH

CH3 N

CH3

Ceftaroline acetate (130)

+

O OO

OO

HOH

H

NS

N

N

S

Tebipenem pivoxil (131)

Tomopenem (132)

NH

NH

NH2N

OH OO

HOH

H

NS

N

O

O

NH

PZ601 (133)

NHOH OO

HOH

H

NS

S

N

ME-1036 (134)

S

NN

OH OO

HOH

H

N

O

N

O

NH2

+

Fig. 3. Microorganism-derived drug evaluation.


96 Brahmachari


Sulopenem (135)

OH OO

HOH

H

NS

SO

O

O

O O

O

HOH

H

N

O

O

H

Faropenem daloxate (136)

OH

NH O

OH

OHCOOHO

O

O

O

OH

OH

OH

Cl

O

NH

NH

O

O

OH

O

NH

O

R

OH

OH

NH

O

NH

OCl

OH

OH

NH

CH3

O

NH

O

O

Teicoplanin analog (137): R = OH

Dalbavancin (138): R = NH

N





OOH

NH2

O

O

O

OH

NH

R

O

OHOH

OH

O

OH

Cl

O

NH

NH

O

O

O

NH

O

OH

OH

OH

NH

O

NH

O

O

NH

Cl

OH

O

NH

O

NH2

Chloroeremomycin (139): R = H

Oritavancin (140): R = Cl

OH

O

O

OH NH2

O

OHOH

OH

O

OH

Cl

O

NH

NH

O

O

O

NH

O

NH

OH

OH

NH

O

NH

O

O

NH

Cl

OH

O

NH

O

NH2

S N

N NH

N

S

N

OH O

N

O

O

HNH2

O

+

TD-1792 (141)



98 Brahmachari


O

O

O

OOH

OHOH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

OH

O

OH

O

OH

O

OHO

NH2

O

NH

OH

O

NH

O

O

NH2

NH

O

NH O O

O

NH2

O

NH

Cl

OH

OO

O

O

OH

O

OHO

O

NH

NH2

O

OHOH

OHOH

Ramoplanin factor A2 (142)

N

NH

O

O

OH

FO

O

N

O

Flopristin (143)

O

N

N

O

N

N O O

NH O

NH

O

N

OH

N

NH

O

O

O

Linopristin (144)





N

O

O

NH

NH

O

O

N

ONH

NH

ONH2

O

NH

O

NH2

COOH

OCOOH

NH

O

NH

O

NH

NH

O

HOOC

Friulimicin (145)

H-Ala-Lys-Gin-Ala-Ala-Ala-Phe-Gly-Pro-Phe-Abu-Phe-Val-Ala-HOAsp-Gly-Asn-Abu-LysOH

S

SS

NH

Duramycin (Moli 901) (146)

OO

OOH

O

OH

O

O

OH

OH

OMe

OHN

Erythromycin (147) Cethromycin (148)

N

OO

O

O

O

O

OHN

O

NHO

O



100 Brahmachari


EP-420 (149)

NNN

O

N

OO

O

N

O

O

O

OH

O

OHN

O

OO

OOH

O

H

O

O

O

OMe

OHN

OMe

OS

NN

N

BAL-19403 (150)

Telithromycin (151)

N

OO

O

O

O

OHN

O

NO

O

OMe

NN

O

O

O

O

OH

OH

O

O

H

O

OH

OH

O

OMe

O OH

Cl

OH

Cl

O

OH

Tiacumicin (152)





N

NH

OH O OH O

OH

NH

OH

H

CONH2

MK-2764 (153)

O

NH

O

OO

OH

O

H2O3PO

OH

O

O

NH

OO

OH

O

OH

OPO3H2

O

O

Rs-DPLA (154)

NH

O

OO

H2O3POO

NH

OO

OH

OPO3H2

O

O

OMe

MeO

Eritoran (155)

N

O

NH

O

OH OH

OH

N

O

OHOH

O

O

MeO

O

NN

NN

O

COOHF

CBR-2092 (156)



102 Brahmachari


NH

NH

NH

NH

NH

O

OO

NH2

O NH

O

OH

O

NH

NH2

O

NH

O

N

O

NHO

NH

OH

OH

OH

NH2

OO

OHO

O

O

N

O

NH

NH2

WAP-829A2 (157)

NH

N

N

OHNH

O

OH OH

NH

O

O

OH

O

OHO

OH

OH

O

NHOH

O

Deoxymulundocandin (158)

O

NH

N

N

OHNH

O

NH

O

O

OH

O

OHO

OH

OH

O

NHOH

O

NH

NH2

Aminocandin (159)





O OH

OH

O

O

OHOH

O O OH OH OH OH

OH

OO

OH

O

NH

NH

R1

R2Patrician A (160): R1 = OH, R2 = H

SPK-843 (161): R1 =NH

N

R2 =N

O

NNH

NH

NNH

O

O

O

O

O

O

NN

NNH

NN

O

O

O

OH

HO

O

R

Cyclosporin (162): R = NIM-811 (163): R =

N N

N

NH

NH

NH O N

H

OHOH

OH

OH

O

O

KRN5500 (164)



104 Brahmachari


NH

OH

OH

R

OH

OH

Galactonojirimycin (165): R = OHMigalastat (166): R = H

ON N

NH

O

NHCH3

OMe

Staurosporine (167)

N

NH

OO

N

O

N

Ruboxistaurin (168)

NNH

NH

NNH

O

O

O

O

O

O

NN

NNH

NN

O

O

O

OH

HO

O

Voclosporin (169)

O

OHOR

OH

O

OH

OOH

Pladienolide D (170): R = Ac

E7107 (171): R = NN

OO

O

NH2 CH3

OHMeO

O

O

O

CH3

O

OH

O

OOH

OH CH3

CH3

Elsamicin A (172)





O

O

O

O

OH

OH

O

OH

OH

OMe

OR

NH2

Doxorubicin (173): R = H

Berubicin (175): R =

O

O

O

O

OH

OH

O

OH

OH

IOHOH

L-Annamycin (174)

O

OHNH2

O

O

O

O

O

OH

OH

O

OH

OH

OH

Sabarubicin (176)

N

O

O

O

O

O

OH

OH

O

OH

OH

OMe

OH

OMe

Nemorubicin (177)

O

NH

N

O

NH

N

N

O

NH

NH

NH2

NH

O

H

Distamycin (178)



106 Brahmachari


O

NH

N

O

NH

N

N

O

NH

NH

NH

O

Br

NH2

NH

Brostallicin (179)

O

O

NH

OR

MeOMeOOH

O

NH2

O

Geldanamycin (180): R = OCH3

Tanespimycin (181): R =

Alvespimycin (182): R =

NH

NH

N

OH

OH

NH

O

MeOMeOOH

O

NH2

O

N

HH +

Cl−

Retaspimycin (183)

OR

OMe

O

N

O

O

OO

OH

MeOO

O

OH

O

MeO

Sirolimus (34): R = H

Deforolimus (Ridaforolimus) (184): R = P

OOH

OH





O

O

O

OH

Cl

Salinosporamide A (185)N

N N

NH

O O

CH3

N

Enzastaurin (186)O

N

ON N

NH

O

OMe

Me

Midostaurin (187)

ON N

NH

O

OH

R

K252a (188): R = COOCH3Lestaurtinib (KT-5555) (189): R = CH2OH KRX-0601 (190)

NHCH3

ON N

NH

O

OMe

OH

Diazepinomicin (191)

N

O

NHOH

OH

OH

NH

N

NH

OMe

Prodigiosin (192)

Me

NH

N

NH

Me

OMe

Obatoclax (193)

S

N

Me

O

O

OH

OO OH

Sagopilone (194)



108 Brahmachari


S

N OHO O

O

OH

Me

Epothilone (195)

S

N OHO O

O

OH

Me

KOS-1574 (196)

NNH

NH

NH

O

O

NPI-2350 (Phenylahistin) (197)

NNH

NH

NH

O

O

NPI-2358 (Plinabulin) (198)

O

OH

OH

OH

Illudin S (199)

O

OH

OH

Irofulven (200)





N N

Anabaseine (201)

N

N

OMe

OMe

DMXBA (GTS-21) (202)

NNH

N

OMe

O

O

ONH

O

O NH

ON

ON

O OHO

O

OO

O

Plitidepsin (203)

O

O

O

O

OO

O

H

H

H

H

H

H

O OO

H

H

H

O

OO

O

H

HO

H

HH

OH

OH

OH

Halichondrin B (204)

Fig. 4. Marine-derived drug candidates under clinical evaluation.


110 Brahmachari


O

OH

H

O OO

H

H

H

O

OO

O

MeO

OH

NH2

Eribulin (205)

N

NH

N

NH

O

O

COOH

Hemiasterlin (206)

E7974 (207)

NH

N

O

O

COOHN

NH

SS

NH

N

Br

OH

OH

O

O

NOH

OH

Br

Psammaplin A (208)

NH

NH

CH3

NH

O

OH

Panobinostat (209)

O

O

O

OMe

O

OAc

OH

O

O

O

OMe

OH OH

OH

O

O

Bryostatin 1 (210)





N

O

O Me

OMe

Me

N

O

O

Me

OAc

MeO

OH

H

Jorumycin (211)

N

OH Me

OMe

Me

N

O

Me

OH

H

O

Me

NH

OCF3

O

O

Zalypsis (212)

NNNN

HN

O O O O O

R

Dolastatin 15 (213): R = N

O

O

O

OMe

Tasidotin (214): R = NH

Dolastatin 10 (215): R =

N

O

NNH

N

O O OMe O

NH

R

OMe

NS

Soblidotin (216): R =



112 Brahmachari


H2N

NH

HN

NH

OO

NH

O

NH

O

O

O

O

O

NH

O

NH

O

N

O

NHO

NH

O

NH

HO

O

NH

R

Kahalalide F (217): R =

O

PM02734 (218): R = O





OH

NH OH OH

NH

OHH2N

O−

OO

OH+

Tetrodotoxin (219)

NGVCCGYKLCHOC

Xen-2174 (220)

NH

NH

HOH

H H

H

H

OSO3H

NH

NH

NH2

Trodusquemine (221)

ILPWKWPWWPWRR-NH2

Indolicidin (222)

ILRWPWWPWRRK-NH2

Omiganan (223)

Fig. 5. Animal-derived drug candidates under clinical evaluation.

8. Concluding Remarks

Natural products continue to play a dominant role in the discovery ofleads for the development of drugs to treat human diseases. Such chemi-cal agents have traditionally also played a major role in drug discoveryand still constitute a prolific source of novel chemotypes or pharma-cophores for medicinal chemistry. Natural product-based scaffolds find keyimportance in drug discovery as well as in optimizing chemical diversity


for human use. The impact of natural products on the developmentpipelines of the pharmaceutical industry is unabated. Despite increasingcompetition from combinatorial and classical compound libraries, therehas been a steady introduction of natural product-derived drugs in the pastyears. Substances like taxol, cyclosporines and the “statins” are corner-stones of modern pharmacotherapy.

We should think of the real scenario that the vast majority of differ-ent natural sources remain virtually untapped. It is estimated that only5–15% of the approximately 250 000 species of higher plants (terrestrialflora) have been investigated chemically and pharmacologically so far;hence, the large areas of tropical rainforests demands for thoroughinvestigation that would unearth tremendous potential at large. Themarine kingdom stands as an enormous resource for the discovery ofpotential chemotherapeutics, and is waiting for its proper exploration.Another vast unexplored area is the microbial world; it has beenreported that “less than 1% of bacterial species and less than 5% of fun-gal species are currently known, and recent evidences indicate thatmillions of microbial species remain undiscovered. “Mother Nature” isthus, an inexhaustible source of drugs and lead molecules. The abundantscaffold diversity in natural products is coupled with “purposefuldesign” — usually to afford an advantage for survival in environmentsthreatening growth and/or survival of producer organism. The quality ofleads arising from natural product discovery is better and often morebiologically friendly, due to their co-evolution with the target sites inbiological systems.

Natural products, thus, still serve as an excellent source for moderndrug discovery and development. The traditional strengths of naturalproducts in oncology and infectious diseases are still ahead from the com-pounds under clinical trials against metabolic and other diseases. Througha medicinal chemistry approach, natural products with low bioactivity orknown compounds can be modified synthetically to improve their phar-macological profiles. A good number of commercially approved drugsoriginated from natural products as well as the huge number of naturalproduct-derived compounds in various stages of clinical developmentindicate that the use of natural product templates is still a viable source ofnew drug candidates.

114 Brahmachari



Acknowledgements

Fruitful and valuable works of numerous researchers worldwide, uponwhich the present manuscript is based, are being acknowledged herein.The author is grateful to all of them regardless their names are enlisted inthe reference section or not.

Abbreviations

AChE acetylcholinesteraseAD Alzheimer’s diseaseADHD attention deficit hyperactivity disorderADMET absorption, distribution, metabolism, excretion, and

toxicityAECB acute exacerbations of chronic bronchitisAIDS acquired immune deficiency syndromeBBB blood–brain barrierCAM complementary and alternative medicineCAP community-acquired pneumoniaCDAD Clostridium difficile-associated diarrheaCDKN1A cyclin-dependent kinase inhibitor 1ACDRI Central Drug Research InstituteCF cystic fibrosisCGRP calcitonin gene-related peptideCIMAP Central Institute of Medicinal and Aromatic PlantsCKD chronic kidney diseaseCOPD chronic obstructive pulmonary diseasecSSSIs complicated skin and skin structure infectionsDNA deoxyribose nucleic acidDTI direct thrombin inhibitorEMEA European Medicines AgencyERT enzyme replacement therapyFAAH fatty acid amide hydrolaseFAH fumaryl acetoacetate hydrolaseFDA Food and Drug Administration (USA)




GLP-1 glucagon-like peptide-1HAP hospital-acquired pneumoniaHCT human colon cancerHCV hepatitis C virusHDAC histone deacetylaseHDL-C high-density lipoprotein-cholesterolHIF-1 hypoxia-inducible factorHIV human immunodeficiency virusHMG-CoA 3-hydroxy-3-methylglutaryl coenzyme AHPPD p-hydroxyphenylpyruvate dioxygenaseHT-1 hereditary tyrosinemia type 1IMPDH inosine monophosphate dehydrogenaseIND investigational new drugLDL-C low-density lipoprotein-cholesterolMAA marketing authorization applicationMetAP-2 methionine aminopeptidase-2mTOR mammalian target of rapamycinNCI National Cancer Institute (USA)NDA new drug application (USA)NET neuroendocrine tumorNF-AT nuclear factor of activated T cellsNSAID non-steroidal anti-inflammatory drugOC ovarian cancerOIC opioid-induced constipationPD Parkinson’s diseasePGE2 prostaglandin E2

PPAR peroxisome proliferator-activated receptorPTP-1B protein tyrosine phosphatase 1BQSAR quantitative structure–activity relationshipRCC renal cell carcinomaRNA ribose nucleic acidS6K1 S6 ribosomal protein kinaseSEGA subependymal giant cell astrocytomaSGLT sodium glucose co-transporterSRT substrate reduction therapySTS soft tissue sarcoma

116 Brahmachari



TCL T-cell lymphomatNOX NADH oxidaseVEGF vascular endothelial growth factorVR 1 vanilloid receptor subtype 1WHO World Health Organization

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