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Chapter 1
General Introduction
2
Light and oxygen are ubiquitous element of our environment with a tremendous
impact on life. Both, the beneficial effects and the harmful effects of light are well
recognized and there is growing awareness of the influence of light (both beneficial
and harmful) on living organisms.1 Recognition of the importance of light in biology
has led to the development of the science of photobiology: the study of the myriad
effects of light on life. Photobiology studies the interaction of light with living
organisms, and the application encompasses a number of areas including
environmental photobiology, photomedicine, and UV photobiology, which is the
study of the effects of ultraviolet radiation on plants, animals and humans.
The interest in human photobiology is currently growing for a number of reasons.
First, sunlight is beneficial to health but overexposure as a result of increased outdoor
activities can cause skin cancer2 and accelerated aging of vital organ.
3 Further,
artificial light sources, such as fluorescent tubes and the new and increasingly popular
high intensity lamps are now used worldwide for lighting of large public shopping
areas, factory-buildings, offices and private houses. As a large part of population
spends much of its time in these artificially illuminated places, in which light intensity
and spectral distribution differ considerably from those found outdoors, there is a
concern about the consequences for human health. Thus, it is not only because of
lamps used for sunbathing that the role of artificial light in human health and diseases
has begun to receive serious attention.4
Second, spectral distribution and intensity of daylight will change if ozone layer in the
stratosphere, which filters out much of the short wavelength UV radiation,5 is
deteriorated by gases from, e.g., spray cans and supersonic aircraft. A change in the
3
spectral distribution and intensity of daylight is expected to have serious
consequences for human health.
Third, xenobiotics (drugs, cosmetics, pesticides etc.) can also interfere in the balance
between light and the human body. The effects may be beneficial and thus the
combination of light and drug can be used as therapeutics. Often however, the effects
are unintended and uncontrolled and damage of organ functions occurs.
Solar UV radiation is divided based on wavelengths into UVA, UVB, and UVC. UVC
(200–290 nm) is filtered out by the atmospheric ozone before reaching the earth. UVB
(290–320 nm) penetrates only as deep as the upper layers of the dermis and primarily
causes erythema or sunburn. UVA (320–400 nm) is capable of transmission through
plate glass and penetrates more deeply into the skin (deeper layers of the epidermis
and dermis) because its longer wavelengths do not scatter as much as the shorter UVB
wavelengths. UVA is particularly important because it makes up 95% of the sun’s UV
radiation reaching the earth’s surface. Photosensitization is generally limited to UV
radiation and visible light. This energy is absorbed by molecules present in the skin
(chromophores) to induce biological responses such as sunburn and drug
photosensitivity.6 Chromophores may be endogenous (e.g., DNA and melanin) or
exogenous (e.g., photosensitizing drugs and chemicals). 7 Most photosensitizing
reactions are activated in the UVA spectrum.
Photobiologists working with ultraviolet radiation are concerned with identifying the
photochemical changes that are produced in living tissue by the absorption of
ultraviolet light and determining the biochemical and physiological responses of cells
to this damage. Today the major challenges to this topic include the elucidation of
4
photochemical reactions involved in photobiology at the molecular level, where
organic photochemistry has a significant role to play.
The human body is exposed to wide array of xenobiotics in one’s lifetime, from food
components to environmental toxins to pharmaceuticals and pesticides. The molecular
mechanism of biological photosensitization by xenobiotics is receiving increasing
attention. The interest in this subject is promoted by the serious toxic reaction
produced by many pharmacologically important chemicals under sunlight irradiation.
Photochemical events produced by the absorption of UV and visible light, and often
in combination with oxygen, play a distinct role in some natural processes of the
metabolism of many xenobiotics, such as pharmaceuticals, prodrugs and drug
metabolites. Photosensitization phenomenon occurs not only in humans, but also in
other organisms. For example, some plants contain potent photosensitizing chemicals.
An increasing number of phytochemicals, including phenols, terpenoids, polyketides,
and alkaloids, are being recognized as photochemically active substances or
photosensitizers. These compounds, unlike the photosynthetic pigments or the
phytochromes, do not have any known function in the plant species in which they
occur. However, when introduced into other biological systems, e.g., cells or complex
organisms, many of them are extremely toxic in light. The cellular targets and the
photochemical processes for some of them have been defined. Certain alkaloids
including furanoquinolines, β-carbolines, cathinones and certain furanochromones
and chromones appear to be of this type: they are photogenotoxic, giving rise to gross
chromosomal aberration in light. A second type of photoreaction, inherently
bimolecular, often leads to oxidations. The accumulation of chemicals of this kind, in
conspicuous quantities in a plant species, suggests roles in deterring or destroying
5
other organisms such as viruses, bacteria, fungi, invertebrates (including insects), and
higher animals.
The number and variety of phototoxic compounds are large. Furthermore, for most
phototoxic xenobiotics a correlation between structure and photoreactivity is not
easily found. It is obvious that, in general, there must be a relationship between
photochemical behaviour and phototoxicity.
It is therefore highly desirable to put on record the photoreactivity of all common
chemicals that may be exposed to sunlight. In the present study emphasis has been
placed on drugs and biologically active plant metabolites.
Drug photochemistry has been the object of a considerable amount of attention,
especially in the last decade. Such interest has been promoted by the fact that even
though many of these compounds are excellent therapeutical agents, they are also
known to often cause photosensitization, which includes phototoxic and/or
photoallergic phenomena.8-10 Over the past decade there has been a considerable
amount of research toward understanding both the unimolecular deactivation pathway
of photoexcited pharmaceutical products and their photosensitizing capability in the
presence of biological substrates, and the molecular mechanism of biological
photosensitization by drugs. Several reviews concerning the mechanisms of both drug
photodegradation and photosensitization were recently published.11-13
With both, phototherapeutics and phototoxicons, the sequence of events, this
eventually leads to the biological effects, starts with the absorption of a photon of
UV-radiation or visible light. In a biological system a photoexcited drug or other
xenobiotics can undergo a number of primary reactions (Fig. 1.1). The detailed
photobiological effects of an excited drug are indicated in Fig. 1.2. As far as the
6
molecular processes underlying the occurrence of photobiological effects are
concerned, there is no essential difference between the phototherapeutics and
phototoxicons as a group; the same processes, a, b and c occur. The processes are:
(a) Photochemical reaction of the compound as such, a unimolecular reaction, e.g.,
rearrangement, isomerization or decomposition. The reaction products or their
metabolites can display their biological activity by interaction with a receptor. At
present there are no reports of phototherapeutic or phototoxic compounds acting in
this way. Yet this can be considered as a possibility; certainly if one takes into
account that interaction of a photometabolite with a receptor is an essential part of a
normal endogenous photobiological processes in man.
(b) Photoreaction with endogenous molecules. An example of this is the irreversible
binding of photoexcited psoralens to DNA as a result of UVA absorption in the
skin. What is considered to play an important role in the so-called PUVA-
therapy.14-17 Photoexcited M can also abstract an electron or an H-atom.
(c) Energy transfer to endogenous compounds. This is exemplified by singlet oxygen
formation from 3O2, which is supposed to play an important role in dye /visible
light therapy of cancer.18-20 Phototoxic compounds of quite different molecular
structure can also produce singlet oxygen by energy transfer, e.g., phenylpropionic
acid derivatives used as anti-inflammatory drugs and tetracyclines.
The photobiological effects which can be observed with a give phototherapeutic or
phototoxicon depends on a variety of factors, such as:
(1) The extent to which each of the primary photoreactions a, b and c occurs.
(2) The extent to which each of the essential bio(macro)molecules is damaged.
7
(3) The bioavailability of the given photoactive compounds and its metabolites, not
only in the organs exposed to light but also at cellular level.
It is commonly assumed that phototoxicity of drugs and other xenobiotics remains
restricted to the organs exposed to light, namely the skin and eyes. However,
there are natural photobiological processes in man by which the eventual effects
occurs in a part of the body far from the sunlight exposed organ in which
photoexcitation of an endogenous compound took place.
M M*
Biological Effect
Rection with endogenous compound
Product formation bya unimolecular reaction Biological effect
Energy transfer toendogenous compounds
Biological Effects
(a)
(b)
(c)
Fig. 1.1
8
Photosensitization Drug/ photosensitizer
Excited State Drug
Triplet State
Energy transfer to
molecular O2
Energy transfer to biomolecule
Excited singlet O2 Oxidation of excitedstate biomolecule
Oxidation-peroxidation ofbiomolecule (lipid, protein) Molecular change
Free raicals
Electron transfer orcovalent binding tobiomolecule
Formation of photoproduct(s)
Molecular change tocell components
Photooxidation of cell components
Toxic reaction withcell components
Damage to critical cell components
Phototoxic skin response
Fluorescence orinternal conversion
hv
hv
DrugDNA
PUVAtherapy
Irreversiblephotobinding of psoalen to DNA
formation of photoproducts
photooxidation of cell components
Toxic reaction with cell components
abnormal prolifrating tissue
Death of cancerous Cells"PDT(photodynamic therapy)"
Fig. 1.2
9
A phototoxic drug can damage the body tissues by formation of radicals or by energy
transfer to endogenous compounds. Oxygen is present in all body tissues, and the
body therefore provides excellent condition for formation of reactive oxygen species.
Cell constituents as proteins, unsaturated fatty acids, cholesterol and DNA are likely
targets for damage caused by ROS. The reactions are often leading to photo
modification of the cell membranes.
To evaluate the photobiological risk of a drug and control of the drug photoreactivity
in practical situations and preparation of protective strategies against the light-induced
damage, it is necessary to understand the involved mechanism. This requires
determination of the excited states generated after light absorption, as well as any
other drug-derived short-lived intermediates and/or reactive oxygen species like
singlet oxygen. Thus, photophysical and photochemical studies, including
examination of excitation and emission properties, identification of reaction
intermediates, isolation of photoproducts, analysis of interaction with biological
substrates, are often an adequate approach to analyze the mechanisms through which
phototoxic effects can be produced. In the following pages a brief overview is made
regarding the mechanisms of phototoxicity induced by drugs.
Absorption of sunlight by drugs leads to their excited states, which will dissipate the
excess energy in a chemical or physical process. Competition between photochemical
and photophysical events ultimately determines to what extent a given excited state
will undergo chemical reactions, or deactivate either radiatively, or by heat
dissipation. The lowest excited singlet and triplet states are bottlenecks in the series of
deactivation processes leading to the ground state. Photo-induced chemical reactions,
10
with a few exceptions, will therefore occur from S1 or T1 as schematically illustrated
in Fig.1.3.
Bio-molecules
Free
radicals
Chemical reactions
Type I
Chemical reactions
Type II
3ΣΣΣΣg
1ΣΣΣΣg
1111∆∆∆∆g
S0
S1
Photosensitizer Oxygen
T1
Fig. 1.3. Jablonski Diagram of general mechanisms of photosensitizer.
Two major types of chemical reactions can occur from the excited states of a
photosensitizer. These are commonly referred to as Type I and Type II reactions (Fig.
1.4). In general, those reactions which involve a photoinduced electron transfer (PET)
between the excited state and the substrate (R) are termed as Type I reactions while
those involving the electronic excitation energy transfer (EET) are the so called Type
II reactions.
11
Fig.1.4. The Type I and Type II reactions of a photosensitizer. Initial events of Type I
and II reactions involve photoinduced electron transfer (PET) and excitation energy
transfer (EET), respectively. While S0, 1S and
3T represent the ground, singlet and
triplet states of the photosensitizer, R represents a biomolecule including oxygen.
Chances of occurrence of both Type I and Type II reactions from the singlet state are
rather remote due to the fact that this state is usually short-lived and any reaction
involving it as a partner should occur within its lifetime (t) which is typically between
nanoseconds and pico seconds. On the other hand, triplet states, which are generated
from the singlet precursor, have a better chance of reacting with other substrates
because they are long-lived (t ranges from microseconds, µs = 10–6
s to milliseconds,
ms =10–3
s) and there is enough time for the reaction to occur subsequent to mutual
diffusion of the reaction partners. The triplets can undergo either electron transfer or
energy transfer reactions with the available substrates. The primary photochemical
steps may or may not be involved in bond-making/bond-breaking, but the subsequent
steps can involve pure chemical reactions giving rise to new products. Most available
data suggest the involvement of an energy transfer reaction between the triplet PDT
photosensitizer and molecular oxygen resulting in the formation of singlet oxygen
(1O2) via the Type II mechanism. Singlet oxygen, 1O2, is unstable with a life time of
12
~6 ms in water and a little longer in lipid and cell environments. Thus, it cannot
diffuse more than a single cell length during its lifetime. However, this reactive
oxygen species is a fairly indiscriminate oxidant that reacts with a variety of
biological molecules and assemblies. Indeed, a large body of evidence exists in the
literature wherein radical products like superoxide radical anion, peroxyl radical,
hydroxyl radical, cation radicals, etc. formed via Type I mechanism have been cited to
be responsible for the observed phototoxic action. In some other cases, participation
of both Type I and Type II mechanisms have been invoked and their relative
contributions depend on the nature the photosensitizer.
The photochemical decomposition of a drug substance will often involve radical
process and/or formation of singlet oxygen. The excited drug molecule can exchange
electrons with another drug molecule, with oxygen or with other compounds present
in the medium. Free radicals formed can subsequently react with new drug molecules,
leading to degradation by several pathways. Excipients or impurities present in the
drug product may also initiate radical chain reactions by absorption of radiation. The
absorbed energy can further be transferred from the excited drug molecule to ground
state oxygen leading to the formation of singlet oxygen which subsequently can
participate in various reactions. Formation of radicals or singlet oxygen in vivo may
cause damage to proteins, lipids, DNA and RNA, and /or cell membranes.
Determination of the detailed photoreactivity characteristics of drug molecule requires
knowledge of the sensitizing and quenching properties of the molecule, e.g.
quenching efficiency of the drug excited state by a substrate, the ability of the drug to
transfer an electron to oxygen and the rate of reaction of the drug radical with ground
state oxygen. A number of techniques have been developed to enable the detection of
13
free radical intermediates, including electron paramagnetic resonance spectroscopy
(EPR) and pulse radiolysis. An infrared luminescence technique is frequently used for
determination of singlet oxygen.21
These methods require specialized equipment. A
more simple approach for studying radical formation is by addition of various free
radical scavengers to the medium during irradiation. The rate of disappearance of the
drug and the appearance of particular products is compared with that occurring
without the scavenger. Polymerization reactions (e.g.,polymerization of acrylamide)
can be used to detect formation of free radicals in anaerobic media. The
photooxidation potential can be studied in terms of oxygen uptake measurements in
the presence of oxidable substrates like histidine and 2,5-dimethyl furan which are
substrates for singlet oxygen, and L-tryptophan which is a substrate for superoxide.
The reactions should be confirmed by addition of suitable singlet oxygen quenchers
and superoxide dismutase. The (lack of) specificity of the various scavengers or
substrates should be taken into account, and a combination of scavengers or substrates
should be used to obtain adequate information. It is important to remember that the
relative reactivity of both the radicals and the scavenger will determine the outcome
of the reaction. If the radical intermediates are extremely reactive, they may react with
the solvent before may other reaction can occur and no change will be observed.
The lifetime of the excited singlet state of a drug molecule is generally of the order of
nanoseconds. This time is normally too short for the excited molecule to react
chemically even with neighbouring molecules, although photoionization can occur.
Excited triplet states of drug molecules can have long lifetime (up to several seconds).
Long-lived intermediates with lifetimes around one second may diffuse between
organelles or to neighbouring cells prior to a reaction with oxygen or endogenous
14
compounds. Excited drug triplets formed in vivo can therefore often reach several
molecular targets prior to de-excitation, implicating a high probability for phototoxic
reactions. The production of singlet oxygen has been reported to occur by energy
transfer both from the singlet and triplet state of a sensitizer. The singlet-triplet
interaction is, however, of very low probability and formation of singlet oxygen by
energy transfer from the triplet state of the sensitizer is highly preferred.
Insight into the molecular processes which a given phototoxicon undergo in vivo after
absorption of UV or visible light, is a prerequisite for the identification of that part of
molecular structure which causes the unwanted photobiological effect. Only after this
identification will it be possible to alter the molecular structure of the xenobiotic in
such a way that the phototoxicity diminishes whereas desired properties remain
conserved. It has been indicated by Beijersbergen van Henegouwen22
that this
research aim can be achieved by combining data from in vitro and in vivo
investigations. The in vivo system is too complicated and without continuous help
from in vitro research, the investigation of this cannot provide much insight.
Photoreactivity of the phototoxic xenobiotic and structural analogues should be
studied:
1. In vitro, whether or not in the presence of essential bio(macro)molecules.
2. In microbiological test systems (e.g., bacteria and yeast) and in cells,
whether or not in culture.
3. In experimental animals or human volunteers.
Both with (1), (2) and (3), attention should be paid to the identification of
photoproducts and to the possibility that photobinding to and damage of
15
biomacromolecules has occurred. These data can provide insight into the formation of
reactive intermediates and into the reaction mechanism occurring in vivo.
With results from in vitro studies (1) and (2) only, it is almost impossible to predict
which photo-induced reactions occur in vivo. This is caused by factors such as:
• Metabolism of xenobiotic. Metabolite can differ in photoreactivity compared
with parent compound.
• (Intracellular) distribution. The amount of xenobiotic that reaches the site of
exposure (e.g., skin or eyes) or specific sites within the cell (e.g., DNA or
membranes of the cell bodies).
• Absorption of radiation by skin components which determines the amount of
light available to the drug.
• Repair processes by which the organism can respond to photochemically
induced damage.
On the other hand, the in vivo system is too complicated and without continuous help
from in vitro research, the investigation of this can not provide much insight. For this
reason, the above mentioned research lines (1), (2) and (3) should be performed in
continuous interaction with each other.
The photochemical studies in the present work are an attempt to address in vitro
photoreactivity of drugs and biologically active plant metabolites. On the basis of
photochemical principles the many photochemical reactions now known have been
rationalized. This is shown in many fine books of photochemistry,23-27
which
demonstrate both the dramatic development of this science in last decades and high
degree of rationalization that has been reached. The photoreactions of drugs28
obviously can be discussed in the same way, and G. M. J. Beijersbergen van
16
Henegouwen22
pointed out some key points that one should take into account. It is
therefore generally possible to predict the photochemical behavior of a new drug, as
of any other molecule, or at least to point out the most likely alternatives. More
exactly, as it has been pointed out by Grenhill,29 it is possible to indicate some
molecular features that are likely to make a molecule liable to photodecomposition,
even if it is difficult to predict the exact photochemical behaviour of a specific
molecule.
At any rate, several chemical functions are expected to introduce photoreactivity
(Scheme 1.1). These are:
(a) The carbonyl group. This behaves as an electrophilic radical in the nπ* excited
state. Typical reactions are reduction via intermolecular hydrogen abstraction and
fragmentation either via α-cleavage (Norrish Type I) or via intramolecular γ-
hydrogen abstraction followed by Cα-Cβ Cleavage (Norrish Type II).
(b) The nitroaromatic group, also behaving as a radical, and undergoing
intermolecular hydrogen abstraction or rearrangement to nitrite ester.
(c) The N-oxide function. This rearranges easily to an oxaziridine and the final
products often result from further reaction of this intermediate.
(d) The C=C double bond, liable to E/Z isomerization as well as to oxidation.
(e) The aryl chloride, liable to homolytic and/or to heterolytic dechlorination.
(f) Products containing a weak C-H bond, e.g., at a benzylic position or α to an
amine nitrogen. These compounds often undergo photoinduced fragmentation via
hydrogen transfer or electron proton transfer.
17
(g) Sulphides, alkenes, polyenes and phenols. These are highly reactive with singlet
oxygen, formed through photosensitization from the relatively harmless ground
state oxygen.
Such functions are present in a very large fraction, if not the majority, of commonly
used drugs. Thus many drug substances, and possibly most of them, are expected to
react when absorbing light.
H
O
H
O H
H
O H
HO O
P r o d u c t s
P r o d u c t s
R - H
( a )
O N O N O 2 N
O H
O
P r o d u c tsR H
( b )
N
OO
N P r o d u c t s
( c )
R
R ''
R R ' '
( d )
A r C l A r + C l
( e )
18
N
C H 2
N
C H
N
O
N
HS e n s
( f )
O 21 O 2
O O H
OO O H
H
N
O O
H O
N
S e n s
( g )
Scheme 1.1
Thus photochemical studies on drugs and promising drug molecules is an vital area of
importance in current medicinal chemistry, for establishing a relation to its
phototoxicity. A satisfactory understanding of this phenomenon requires a detailed
knowledge of the photochemistry of such molecules. In principal, photooxidation
reactions can only be anticipated on the basis of good knowledge of the possible
photochemical mechanisms. To achieve this goal different types of study have to be
undertaken:
(a) Photophysical studies− light absorption and emission (fluorescence,
phosphorescence) to determine the nature of involved excited states, as well as
their energies. Laser flash photolysis for detection of triplet states of other short-
19
lived transition species that could interact with biomolecules. Singlet oxygen
detection (steady state or time resolved near infrared emission).
(b) Photosensitized reactions of biomolecules− photodynamic lipid peroxidation,
photomodification of proteins (protein photocrosslinking, drug protein
photobinding) drug photosensitizer DNA damage (strand breaks, oxidative
damage to bases, pyrimidine dimers).
(c) Photochemical studies− photostability, photodegradation (isolation and
identification of drug-derived photoproducts by chromatography and
spectroscopy, product-based elucidation of the photochemical mechanisms.
(d) Photooxidation of drug molecules with singlet oxygen.
In the present work we have undertaken two of the above aspects ‘C’ and ‘D’ of the
drug photochemistry using some representative examples from established drugs and
promising drug (biologically active molecules) class.
20
A collection of literature is presented here which illustrate the various in vitro
photoreactions of the various drugs and related substances.
Anti-histaminic and immunosuppressant drugs:
Among drugs with anti-histaminic action are thiazine derivative promethazine (1),
which upon irradiation gets, N-dealkylated to phenothiazine (2) which in turn is
oxidized to the sulfone (3) and to the 3Hphenothiazine-3-one (4) (Scheme 1.2).30
Antihistaminic drug terefenadine(5) undergoes oxidation (main process) and
dehydration at the benzylic position to give products (6) and (7), respectively, upon
irradiation in aqueous solution31
(Scheme 1.3).
N
S
Me
NMe2
NH
S
NH
S
N
S Ohv hv
O
(1) (2) (3) (4)
Scheme 1.2
NHOPh2C (CH2)3CH
OH
tBu
NHOPh2C (CH2)3C
O
tBu NHOPh2C (CH2)3 CH
CH
tBu+
(5)
(6) (7)
hv
Scheme 1.3
21
The immunosuppressant drug azathioprene (8) undergoes fragmentation of the C-S
bond to give 6-mercaptopurine (9) and 1-methyl-4-nitro-5-hydroxyimidazole (10) as
well as cyclization reaction to give (11)32
(Scheme 1.4).
N
N N
N
S
N
N
NO2
Me
H
N
N N
N
SH
H
N
NOH
NO2
MeN
N N
N
SN
NMe
+ +hv
H2OpH = 7 or 3
(8) (9) (10) (11)
Scheme 1.4
Non steroidal anti-inflammatory drugs:
A variety of 2-aryl propionic acid derivatives are used as anti-inflammatory drugs.
Most of these are photoreactive and have some phototoxic action. As a consequence,
their photochemistry has been intensively investigated.33-35
The main process in
aqueous solution is decarboxylation to yield a benzyl radical, a general reaction with
α-arylcarboxylic acids.36
Under anaerobic conditions, benzyl radical undergo
dimerization or reduction (and in an organic solvents abstracts hydrogen).37
In
presence of oxygen, addition to give hydroperoxy radical and the corresponding
alcohol and ketone.38
ArCHRCOOH ArCHR ArCHR]2, ArCH2R etc
ArCHROO ArCOR, etc
Scheme 1.4
22
MeO
CHCOOH
MeMeO
CH2Me
MeO
CHOH
Me
MeO
COMe13 + 14 +
(13) (14)
+
hv
H20
Ar
O2(12)
(15)
Scheme 1.5
The results from the irradiation of naproxen (12) in water are shown in Scheme (1.5),
and a related chemical course is followed with several drugs pertaining to this group,
such as ibuprofen,39
butibufen,40
flurbiprofen,39
ketoprofen,41,42
suprofen,43
benoxaprofen,40,44
tiaprofenic acid45
and ketorolac tromethamine (16)46
(Scheme 1.6).
NPhCO
COO NHC(CH2OH)3
hv
EtOH or H2ON
X
PhCO
X = CH2, CHOH, CHO2H, CO
(16) (17)
Scheme 1.6
For Indomethacin (18) in methanol decarboxylation is the main process,47,48
when
mercury lamps are used, while day light irradiation leads to products conserving the
carboxyl group which have been rationalized as arising via the acyl radical (Scheme
1.7)49
. In case of the related drug diclofenac (19), on the other hand, dechlorination as
stated above is the dominant process. Sequential loss of both chlorine atoms is
23
followed by ring closure, reasonably via radical addition, to yield the carbazole-1
acetic acid (20) and (21) as main products (scheme 1.8).50
The anti-inflammatory
agent meclofenamic acid (22) likewise undergoes dechlorination and ring closure to
the carbazoles (23) and (24) (Scheme 1.9).51 Vargas et al.52a carried out irradiation of
ethanolic solution of the photoallergic and phototoxic anti-inflammatory and
analgesic agent aceclofenac (Airtal), is photolabile under aerobic and anaerobic
conditions. Eriksson et al.52b also studied the photolytic transformation of diclofenac
and its transformation products in aqueous solution.
Photoreactivity has been reported also for some anti-inflammatory and analgesic
drugs different from aryl acetic acid.53-55
The photochemistry of analgesic drug phenazopyridine hydrochloride (25) studied
by Jawaid et al.56
in different reaction media and gave 26, 27, 28 and 29 as products
(Scheme 1.10).
N
MeOCH2COOH
Me
COC6H4-4-Cl
N
MeOCH2COOMe
COC6H4-4-ClN
MeOCH2
COC6H4-4-Cl
O
O
C
O
N
MeOR
Me
COC6H4-4-Cl
Day light
MeOH
Hg Lamp
MeOH
R = Me, CHO
+
(18)
Scheme 1.7
24
NH
Cl
Cl
HOOCH2C
N
H
CH2COOH
N
H
HOOCH2C OH
hv
H2O or MeOH
+
(19) (20) (21)
Scheme 1.8
NH
Cl
Cl
HOOC
N
H
COOH
N
H
HOOC Cl
hv +
MeCl
Me
Me
(22) (23) (24)
Scheme 1.9
H2N NH2N
N N
(25)
NNH2
NH2
H2N NH N NH2H2N
NH2NN
N
NH2
NH2N
NH2
NH2
O NH2
HCl
+ + +
(26) (27) (28) (29)
hvCH3OHor H2Oor drug adsorbed onsilica gel
Scheme 1.10
25
Glucocorticosteroides:
The photoreactivity of glucocorticosteroids have been explored both in solution as
well as in solid state and it is well known that they have to be protected from light.
Hydrocortisone (30), cortisone (32) and their acetates (31, 33) undergo
photooxidation in the solid state. The main process involves loss of the side chain at
C-17 to give androstendione and trione derivatives respectively (Scheme 1.11).57
Molecular packing has an important role in determining the photostability in the solid.
As an example irradiation of crystalline hydrocortisone tert- butylacetate leads to the
photooxidation of two over five of the polymorphs investigated. This fact has been
correlated with the possibility of oxygen to penetrate in the crystal in such structure.58
Photodegradation of hydrocortisone 21-acetate (HCA)59
have been also studied in
methanol solution under UV B light.
X
O
COCH2ROH
X
O
O
hv,N2
solid
X= COH
H
R= H
R=OAcX= CO
R= H
R= OAc
(30)
(31)
(32)
(33)
Scheme 1.11
26
Cross conjugated glucocorticosteroids such as prednisolone (34), prednisone (35),
betamethasone (36), triamacinolone (37) and others are quite photoreactive, as one
may expect, since the efficient photorearrangement of cyclohexadienones to
bicyclo[3.1.0] hexanones is well known.60 This rearrangement has been observed for
dexamethasone, prednisolone, prednisone, betamethasone and some of their acetates
(Scheme 1.12).61,62 The primary photoproducts may undergo further transformation
with cleavage of the three membered rings resulting in re-aromatization or cleavage of
ring A or in expansion of ring B.
X
O
COCH2OROH
R'
R''
solid
X
COCH2OROH
R'
R''O
hv
X R R' R''
H, Ac
H, Ac
H, Ac
COH
H
COH
H
COH
H
CO
H
H
H
H
H
F
F
Me
Me
(34)
(35)
(36)
(37)
Scheme 1.12
27
The photochemistry of anti-inflammatory drug clobetasol propionate (38) was
studied in aerobic as well as in anaerobic condition, which produces 39, 40 and 41 as
a major photoproduct (Scheme 1.13).63
Dseonide also shows similar type of reaction
pattern. 64
O
H3C
HO CH3
CH3
F
O
ClO
O
H3C
HO CH3
CH3
F
O
ClO
O
O
H3C
HO
CH3
F
O
OOH O
O
H3C
HO
CH3
F
O
ClO
O
hv (254 nm)
MeCN or 2-propanol,
HO
hv (310 nm)2-propanol,argon
hv (310 nm)O2, 2-propanol
(38) (39)
(40)
(41)
Argon or oxygen
39
39 +
+
(minor)
(major)
(minor)
(major)
Scheme 1.13
Drug acting on central nervous system:
5,5-Alkyl derivatives of barbituric acid (42) are used as hypnotic and tranquillizers.
These compounds undergo two types of photochemical reactions (Scheme 1.14). In
first type of reactions cleavage of the C(4)-C(5) bonds takes place which leads to the
formation of an intermediate isocyanate (path a), which in turn adds nucleophilic
solvents to give an amide (43) in water and urethane (44) in ethanol. The positive
28
evidence for the formation of isocyanate has been obtained by irradiation in the solid
state.65
Barton et al.66
studied similar type of reaction pattern in case of barbital (45,
R, R’=Et, R’’=H) and its methyl derivative (46, R, R’=Et, R’’=Me). The second one
involves cleavage of second C-C bond with the elimination of CO (path b). Barton et
al.67,68 obtained similar reaction pattern with mephobarbital (47, R=Et, R’=Me,
R’’=H) which leads to hydantoin (48) as product. Different process occurs for the
acidic forms of cyclobarbital (49), which is photooxidized to ketone (50) rather than
cleaved (Scheme 1.15)
N
NHR'
R
R''
O
OO
CH
N
NR'
R
R''
OO
CO
CHRR'
N
NHCOOH
R''
OO
CHRR'
N
NH2
R''
OO
CHRR'
N
NHCOOEt
R''
OO
N
NO
O
HR'
R
R''
N
NHR'' or R
H
R''
O
OO N
NHR'' or R
OH
R''
O
OO
path a
path b
path c
hv
H2O
EtOH
(42)
(43)
(44)
(48)
(53)
Scheme 1.14
29
For the tranquillizer proxibarbital (51) it was suggested that a nucleophilic group in
the side chain intervenes in the process via intermolecular addition and gives the
tetrahydrofuran (52) (Scheme 1.16).69
Monoalkylbarbiturates (53) undergo
hydroxylation at position 5.70 2-Thio analogue of Phenobarbital (54) gives (55) by
selective reduction of the thiocarbonyl function by irradiation in alcohols (Scheme
1.17).71 DellaGreca et al.72 also observed the phototransformation of the drug
trazodone in aqueous solution.
N
NH
O
OO
Et
H
N
NH
O
O
Et
H
hv
O
O
(49) (50)
Scheme 1.15
N
NH
O
OO
R''
Me OH
OO
Me
H2NOCHNOC
hv
(51) (52)
Scheme 1.16
30
N
NH
O
SO
Ph
Et
H
N
NH
O
O
Ph
Et
H
hv
i-PrOH
(54) (55)
Scheme 1.17
Benzodiazepines:
They are generally photolabile, but the path followed in the degradation depends on
the structure of each derivative and on the reaction condition. Moore et al.73
obtained
benzophenone (57) as main product by the irradiation of diazepam (56) at 300 nm in
MeOH-H2O through the cleavage of heterocyclic ring, and dihydroquinazoline (58)
by irradiation at 254 nm in methanol. This compound then slowly isomerizes to (59)
as well as to (60) and (61) through dechlorination and oxidation (Scheme 1.18).
N
N
Ph
MeO
N
NCl
Ph
Me
N
NCl
Ph
Me
N
NR
Ph
Me
O
COPh
NHMe
Cl
(57) +
hv, 254 nm
MeOH/H2O
hv, 320 nmMeOH/H2O
(56)
(57)
(58)
(59)
(60) R=H, (61) R=Cl
pH= 7.4
Scheme 1.18
31
Andersin et al.74,75
studied intravenous anaesthetic midazolam (62) which undergo
ring restriction to quinazoline (63) as well as oxidation to 5-fluorophenyl moiety to
give (64) and (65) (Scheme 1.19). Roth et al.76
obtained different reaction pattern in
case of nitrazepam (66) because of the insertion of nitro subsistent, this abstracts
hydrogen and reduced to azoxy, azo and amino function by irradiation in organic
solvents under nitrogen. The hypnotic flunitrazepam (67) undergoes a multi step
reduction finally 60 leading to the 7-amino derivative under anaerobic conditions.77,78
While it is N-demethylated to give (68) in presence of oxygen (Scheme1.20).77
N
N
N
F
Cl
Me
N
NH
N
Cl
Me
O
N
N
Me
Cl
F
N
NH
Me
Cl
O
hv
H2O+ +
(62) (63) (64) (65)
Scheme 1.19
N Nhv
+
+N
N
O
O2N
R
Ar
Ar =Ph, R= H
Ar = 2-F-C6H4, R = Me
Ar = 2-F-C6H4, R = H
(66)
(67)
(68)
N
N
OR
Ar
N
N
OR
Ar
N
N
O
H2N
R
Ar
N N
N
N
OR
Ar
N
N
OR
ArO
Scheme 1.20
32
Chlorodiazepoxide (69) in which photochemically active moiety N-oxide is present
rearranges to oxaziridine (70) and further reacts to give compound (71) and (72)
through ring contraction and ring expansion respectively.79,80
The solid state
photochemistry of chlordizepoxide 81 gave quinazoline (71) and ring opened product
(74) and (75). Cornelissen 82 also studied same compound in presence of reducing
agent such as glutathione where the main observed process is N-deoxygenation to
(73) (Scheme 1.21).
N
N
NHMe
Cl
Ph
N
N
NHMe
Cl
Ph
N
N
NHMe
Cl
Ph O
Cl
Cl
N
N
COPh
NHMe
N
N
O
NHMe
NHMe
Ph
Cl
O
Cl
N
N
O
NHMe
Ph
hv
Solution
hv
GSH
hv, Solid
GSH
(69)
(70)
(71)
(72)
(73)
(74) (75)
(71) + +
Scheme 1.21
33
Antihypertensives:
4-nitrophenyldihydropyridines are widely used as vasodilators and due topresence of
hydrogen abstracting nitro group and easily abstracting benzylic hydrogen these drugs
are considered to be quite photoreactive. Reduction of nitro to nitroso group of
heterocyclic ring and re-oxidation of nitroso group in the presence of oxygen are
mainly observed reaction paths (Scheme 1.22). Nifedipine (76), the 4-
nitrophenyldihydropyridine derivative, shows similar type of reaction pattern.83-85
Other nitrophenyldihydropyridine such as nicardipine (77),86
furnidipine (78) 87
and
nimodipine (79) 88
also photoreact in the similar manner. Fasani et al. 89
investigate
the photochemical degradation of amlodipine in water and in organic solvents.
N
COOR
Me
H
Me
R'OOC
NO2
N
COOR
MeMe
R'OOC
NO
N
COOR
MeMe
R'OOC
NO2
hv
solution or solid
O2
(76) R,R' = Me, 2-NO2 (77) R= Me, R' =[(N-methyl-N-benzyl)-2-aminoethyl](78) R,R' =Et, 2-tetrahydrofurylmethyl (79) R, R' =iso-propyl, 2-methoxyethyltetrahydrofurylmethyl
Scheme 1.22
34
Diltiazem is stable in solid state 90
but on irradiation of aqueous solution at different
pH it gets deacetylated. Karlicek et al., 91
on irradiation of aqueous solution of
ergotamine under nitrogen atmosphere, obtained product due to hydration of double
bond at 9,10 position. Reserpine (80) photoreacts both in aqueous solution and in
chloroform and the process occurring are epimerization at C-3 and stepwise
dehydration of the tetrahydro carboline skeleton 92,93 (Scheme 1.23).
N
N
MeO OMe
OMe
MeO H
MeOOC
H
HOMe
OH
NNH
NN
NN
hv
H2Oor CHCl3
(80)
Scheme 1.23
Antibacterials:
Golpashin et al. 94
studied several N-substituted sulfanilamide derivative and reported
that yields of products changes with the structure. The main process takes place is the
cleavage of C-S and S-N bonds with the elimination of SO2 and formation of aniline
(81) and appropriate amine (82) (Scheme 1.24). Chiang et al. 95 observed that
methylation of amino group take place on irradiation of sulfadimetoxine in methanol.
Irradiation of sulfacetamide (83) in water yielded deacetylated product sulfanilamide
(84), which undergoes oxidation of the amino group to give the azo (85) and the nitro
(86) derivative,96
when irradiated in water. In ethanol97
the formation of 2-
methylquinoline-6-sulfonamide (87) accompanies the above process (Scheme 1.25).
35
SO2NHRH2N
NH2
RNH2+hv
R = NHBuC
O
C NH2
NH N
S
N N N
S
N N
OMe
OMe
(81) (82)
Scheme 1.24
NH2
SO2NHAc
NH2
SO2NH2
N = N
SO2NH2
NO2
SO2NH2
N
H2O2NS
Me
(in EtOH)+ +hv hv
H2Oor EtOH
(83) (84) (85) (86) (87)
H2O
Scheme 1.25
Darvis et al.98
and Moore et al.99
carried out irradiation of aqueous solution of
tetracycline (88) under aerobic condition where homolytic deamination with the
addition of oxygen, resulted in the formation of quinine (89) (Scheme 1.26).
Chlorotetracycline on irradiation in aqueous buffer solution at pH 7.4 undergo
homolytic dechloroniation.100
MeHO
OH O O
CONH2
OH
NMe2H
OHOH O
OH
CONH2
O
OH
CONH2
OO
O
OH
CONH2
O
O2
hv
(88) (89)
Scheme 1.26
36
Aqueous solution of chloramphenicol (90) gives 4-nitrobenzaldehyde (91), glycolic
aldehyde (92) and dichloroacetamide (93) by the homolytic cleavage of C-C bond.
The resulting product 4-nitrobenzaldehyde undergoes secondary photoreaction and
leads to amino and nitro benzoic acid as well as aminobenzaldehyde oxime 101-103
(Scheme 1.27).
CHCHCH2OHO2N
OHNHCOCHCl2O2N CHO
CHO
CH2OHCHCl2CONH2+ +hv
(90) (91) (92) (93)
Scheme 1.27
The urinary anti-bacterial nitrofurantoin (94) is cleaved to nitrofuran carboxaldehyde
upon UV irradiation. Furazolidone (95) is cleaved and hydrolyzed to nitrofuran
carboxaldehyde (Scheme 1.28).104 Fasani et al.105 studied the photochemistry of
oxazolidinone antibacterial drugs in water and methanol.
O CHO2N N NY
X
O
O CHOO2NNO2CH2OCH2CH NNHCONH2+
hv
(94),X = NH, Y = CO(95),X = O, Y = CH2
Scheme 1.28
Among five membered heterocycles metronidazole (96) and related antibacterials
show typical nitro group photoreactions.106-108 This is initiated by typical nitro nitrite
37
rearrangement to give (97) followed by shift of NO group to vicinal position.
Hydrolytic ring opening-ring closure from oxime leads to 1,2,4-oxadiol-3-
carboxamide (98) which finally hydrolyzed to oxaldiamides (99) (Scheme 1.29). A
different photochemistry of metronidazole was observed in presence of citrate.109
Irradiation of six membered heterocyclic drug isoniazid (100) in ethanol caused
oxidation of ethanol to acetaldehyde which is trapped by substrate to yield hydrazone
(101) which again reacts with a molecule of ethanol to give (102)110 (Scheme 1.30).
Trimethoprim111
(103) undergoes oxidation at benzylic position and hydrolysis of
amino group in pyrimidine ring to yield (104) and (105) (Scheme 1.31).
N
N NO2Me
R
N
N ONOMe
R
N
N OHMe
R
NO
N
NMe
R
O
NOH
Me NH
O
N
OH
OH
RN
N
NOMe
NHR
O
O
NH2
O
RHN
hv
H2O
hv
(96) (97)
(98)(99)
Scheme 1.29
N
CONHNH2
N
CONHN=CHMe
N
CONHNHCHCHMe
OH
Me+hv
EtOH
(100) (101) (102)
Scheme 1.30
38
N
N
OMe
MeO
MeO
NH2
NH2
N
N
OMe
MeO
MeO
NH2
NH2
N
N
OMe
MeO
MeO
OH
OHO
+hv
(103) (104) (105)
Scheme 1.31
Fluoroquinolones:
Quinolone antibiotics bearing fluorine substituent, such as norfloxacin (105a) are
commonly called fluoroquinolones. The photobehaviour of fluoroquinolone
antibiotics has recently been the object of increasing interest due to the finding of
their photosensitizing properties.112
The main result obtained for a series of
structurally related, representative fluoroquinolone drugs is reviewed.113
Both
activation of oxygen and various degradation pathways have been identified and the
effects of medium and structure have been rationalized. The results can help in the
understanding of the photochemistry occurring in biological environments and in the
assessing of the correlation between structural characteristics and biological
photodamage.
Antiprotozoal drugs:
Photochemistry of antiprotozoal drug quinine occurring in citric acid solution has
been extensively studied114
and this drug is well known to be photolabile.115
Photochemical oxidative degradation of alkyl amino chain is the main reaction path
observed in the majority of this class drug. 6-Alkylamino derivative primaquine
(106),116,117
4-alkylamino derivative amodiaquine,118
hydroxychloroquine (107)119
and chloroquine (108)120-122 undergo degradation of alkylamino side chain (Scheme
39
1.32, 1.33 and 1.34). Tonnesen and Grislingaas123
found that mefloquine (109), on
irradiation in methanol produces (110) and (111) as main product (Scheme 1.35).
N
NHCH(CH2)3NHMe
Me
MeO
N
NHCHX
Me
MeO
X = CH2COCH2NHMe,
COCH2CH2NHMe,
COCH+CHNHMe,
CH2COCH+CH2,
hv
H2O, pH= 7.4
(106)
Scheme 1.32
N
NHCH(CH2)3N
Me
Cl
hv
H2O
CH2CH2OH
Et
N
NHCH(CH2)3X
Me
Cl
+ Further Products
X = NHEt, NHCH2CH2OH, H(107)
Scheme 1.33
N
NHCH(CH2)3NEt2
Me
Cl N
NHCH(CH2)2X
Me
Cl N
Y
Cl
X = CH2NHEt, CH2NAc, OH Y = NH2, O-i-Pr, Et
+hv
i-PrOH
(108)
Scheme 1.34
40
N
NH
CF3
N
X
CF3
X = COOMe
X = CH2OH
hv
(109)
(110)
(111)
Scheme 1.35
Antineoplastic drugs:
Horton et al.124 observed that irradiation of decarbazine (112) in solution causes
dimethylamine elimination to yield diazo derivative (113), which is further
hydrolyzed to give hydroxyimidazole (114). This hydroxyimidazole in turn couple
with diazo derivative (113) to give azo derivative (115). Alternatively (113) cyclize to
give 2-azahypoxanthine (116) (Scheme 1.36).
N
NH
CONH2
N=NNMe2
N
N
CONH2
N2
N
N
CONH2
N=NNH
N CONH2
OH
N
NH
CONH2
OHN
N
NHN
NH
O
hv
H2O
(112)(113)
(114)
(115)
(116)
Scheme 1.36
41
An investigation of photochemistry of anti-tumor antibiotics, hedamycin and
kidamycin has been reported.125
6-Mercaptopurine (117) is oxidized when irradiated
in oxygen equilibrated aqueous solution by near U.V light giving sulfinate (118) as
the primary product, which is finally oxidized to sulfonate (119) (Scheme 1.37).126
Several other anti-neoplastic drugs as alkaloid vinblastine sulphate, carmustine,
tauromustine and mitonaftide were found to be photochemically unstable.
N
N N
N
SH
H
N
N N
N
SOOH
H
N
N N
N
SO3H
H
hv
O2, H2O
(117) (118) (119)
Scheme 1.37
The neuroleptic drug levomepromazine is photolabile under UV-A and UVB light in
aerobic conditions. Irradiation of a methanol solution of this drug produces one
photoproduct, resulting from the oxidation of levomepromazine. It is demonstrated
that photodegradation occurs via type II mechanism involving irreversible trapping of
self-photogenerated singlet molecular oxygen.127
The photoreactivity of phototoxic anti cancer drug flutamide has also been studied in
homogenous media, cyclodextrin cavity and liposomes.128,129
Jawaid et al.130 found that antiviral drug acyclovir (120), on photodegradation in
aqueous solution produces 121 , 122, and 123 as a photoproducts (Scheme 1.38).
42
hv, O2
H2O
HN
N N
N
O
H2NR(120)
HN
N NH
NH
OO
O NHR
(121)
+N
HNHN
O
NHR
+N
OH2N
H2N O
NHR
(122) (123)
R= OOH
Scheme 1.38
Gonadotropic steroid and Synthetic estrogens:
Synthetic estrogens are generally the stilbene derivatives. They undergo fast E-Z
photoisomerization, and trans fused dihydrophenanthrene is formed by the
conrotatory electrocyclic ring closure of the Z-isomer, which in turn gets aromatized
in presence of oxidants such as atmospheric oxygen. Thus clomiphene (124a), when
irradiated in chloroform solution gives phenanthrenes (125) and (126) (Scheme
1.39).131
Cyclization is also observed with temoxifen (111b).132
Dihydroxy substituted
stilbenes such as dienoestrol (114) and stilboestrol (115) are like wise cyclised133-135
(Scheme 1.40 and 1.41)
43
Et2N(H2C)2O
Ph R
Ph
Et2N(H2C)2O
Ph R
R
Et2N(H2C)2O
+hv
CHCl3
(124a), R=Cl(124b), R= Et
(125) (126)
Scheme 1.39
Me
Me
OH
HO
OO
Et
H H
CH2
hv
MeOH, H2O
(127)
Scheme 1.40
EtEt
OHHO
OO
Et Et
H H
hv
AcOH, H2O
MeOH, H2O
Et
Et
OH
HO (128)
Scheme 1.41
44
The phenolic ring present in the estrogens makes them quite labile to photooxidation.
The reaction can be conveniently carried out by photosensitization, under conditions
where singlet oxygen is produced avoiding direct irradiation of the substrate. Sedee
and co-worker136 observed that photosensitized reaction of estradiol (129) involve
singlet oxygen addition to electron rich phenolic ring to yield ketohydroperoxide
(130). Similar reaction pattern was obtained in case of estrone (131)137 (Scheme1.42).
X
HO
MeX
O
Me
HOOhv
O2
X = C
OH
C CH
X = C O
(129) (130)
(131)
Scheme 1.42
When photolysis is carried out in solid state different reaction paths are observed.
Reisch et al. 138,139 have reported that testosterone (132) yielded androstenedione
(134) and androstanedione (135), while 17- methyltestosterone (133) gives
secoderivative (136) (Scheme 1.43). Levonorgestrol and ethisterone are
photodimerized in solid state under nitrogen atmosphere.140,141
Testosterone
propionate (137) gives dimer (138) when irradiated in solid state (scheme 1.44).142a
Svanfelt et al.142b
observed the photochemical transformation of the thyroid hormone
levothyroxine in aqueous solution.
45
O
Me
Me
OH
R
O
MeO
O
Me
Me
O
Me
Me
O O
H
hv
Solid
R = H
R = Me
R = H
R = Me
+(132)
(133)
(136)
(134) (135)
Scheme 1.43
O
Me OCOEt
Me O
Me OCOEt
Me
Me
MeEtOCO
HO
hv
(137) (138)
Solid
Scheme 1.44
Anti-diuretic Drugs
The phototoxic diuretic drug furosemide (139) is photolabile under aerobic and
anaerobic conditions. Irradiation of methanolic solution of furosemide under oxygen
atmosphere gave photoproducts 140, 141a, 141b and 142, while under argon
atmosphere the photoproduct 140 and 141a were isolated143 (Scheme 1.45). A
peroxidic unstable product was also detected during the photolysis under oxygen
atmosphere. Furthermore, a photocycloaddition of singlet oxygen to furan group of
furosemide was also detected.
46
COOH
H2NO2S
Cl
NHCH2O
COOH
H2NO2S
NHCH2O
R
H2NO2S
Cl
NHCH2O
COOH
H2NO2S
Cl
N+
OO
O
(139)
(140)
(141a), R= H(141b), R= OH
(142)
+ 141a
140 +
hv
Ar
hv
O2
Scheme 1.45
The phototoxic diuretic drug chlorthalidone (143) is photolabile under aerobic
conditions and UVB light.144,145
Irradiation of this drug under oxygen atmosphere
produce photoproducts 144, 145, 146 and singlet oxygen (Scheme 1.46).
NH
O
HOCl
SO2NH2
NH
O
Cl
NH
O
NHOH
OH
O
O
+ +hv
1O2
(143) (144) (145) (146)
Scheme 1.46
The phototoxic antidiabetes drug glipizide, a benzosulfonamide derivative, was also
photolabile under aerobic conditions and UVB light.146
Vargas et al.147
found that the
phototoxic antidiabetes drug gliclazide (147) is photolabile under aerobic conditions
and UV-B light (Scheme 1.47).
47
N S
O
O
CH3NH
O
NH
Gliclazide (147)
hv
N NH2
(148) (149)
S
O
O
CH3H
O
NH
Scheme 1.47
Hydrochlorothiazide (150) dimerized148 upon irradiation with a medium pressure Hg
arc lamp through a glass filter in deaerated aqueous or alcohol solution to give (151)
(Scheme 1.48). Amiloride (152), another potency diuretic drug shows a similar
behavior under irradiation in UVA-vis region, producing dechlorination (Scheme
1.49).
NH
NHS
OO
H2NO2S
Cl
HN
HNS
O O
Cl
NH
NHS
OO
Cl
(150) (151)
Scheme 1.48
48
N
NCl
H2N
CONH
NH2
C
NH
NH2
N
N
H2N
CONH
NH2
C
NH
NH2
(152) (153)
Scheme 1.49
Photooxidation of troglitazone, an antidiabetic drug, gave the quinone and quinine
epoxide as the major products.149 Photooxidation of the ophthalmic drugs pindolol
and timolol in water was reported to involve singlet oxygen.150 Photooxidative
degradation of papaverine 151 and clomipramine 152 has also been reported.
Plant derived natural products
The neem triterpenoid nimbin (154) on photo-oxidation produced two isomeric
products (155, 156) containing a hydroxybutenolide moiety, formed by the reaction of
singlet oxygen with the furan ring (Scheme 1.50).
HOH
O
O
O
HO
O
O
OH
+
(154) (155) (156)
1O2
Scheme 1.50
Photosensitized oxygenation of two plant derived terpenoids furanoeremophilane
(157) and tinosponone (161) have been also studied by Jawaid et al.(Scheme 1.51 and
1.52).154,155
49
ORH
ORH OH
O
ORH
O O
(157) (158) (159)
+
OH
OOH
(160)
H
OCH3
O2, [Psi] -Rose bengal
O2, hv
O2, hv, Benzene
Sens/Methanol
Sens/Methanol
or
R
O
O
R =
Scheme 1.51
OO
HO
O
O
O
H
OH
O
O
H
O
O
O
HOO
OCH3
O2, hv/ Sens
+
(161)(162) (163)
O2, hv/ Sens
Benzene
Methanol
(164)
RR R
R
R=
Scheme 1.52
50
Latifolin (165), the major constituent of D. latifolia on photolysis gave trans- 1-(2,4-
dimethoxy-3-hydroxyphenyl)-2-(2-hydroxyphenyl) cyclopropane (166) as the sole
photo di-Π-methane rearrangement product. In contrast, its analogues, 3-(2,4,5-
trimethoxyphenyl)-3-phenyl-prop-1-ene (167) and 3-(2,4-dimethoxyphenyl)-3-
phenyl-prop-1-ene (168), gave 1:1 mixture of cis- and trans-cyclopropanes. Dye-
sensitized photooxidation of latifolin and dihydrolatifolin (169) gave novel xanthan
derivatives (170) and (171) involving a crucial step of photooxidative demethylation
followed by cyclization. Similar reaction of the closely related propenyl compound
172 gave, interestingly the benzofuran (173). The propane (174), lacking free
hydroxyl or double bond, gave only the quinone (175) indicating that quinones are
intermediates in the above oxidations. The cinnamyl alcohol (176), having similar
feature, undergoes oxidation to the corresponding aldehyde (177) and the
benzophenone (178) but not to a quinone (Scheme 1.53).156
51
OCH3H3CO
R1
R2
(165), R1=R2=OH(167), R1=OCH3, R2=H(168), R1=R2=H
O
R
H3CO
HO
170, R= CH=CH2
171, R= CH2CH3
OCH3H3CO
HO
(169), R1=R2=OH(174), R1=OH, R2=H
OCH3H3CO
HO
172
H3CO
R1
HO
H3CO
OH3CO
O
R2H3CO
R1
R3
176, R1=R3=H, R2=OH, R4=CH2OH177, R1=R3=H, R2=OH, R4=CHO
178, R1=R3=H, R2=OH,
(166)
(173)
OHH
H
OCH3
R2
OCH3
(175)
R2H3CO
R1
O R3R4
Scheme 1.53
3-Substituted cholesterols (179) and 7-substituted pseudocholesterols (179a) undergo
a facile photooxygenation sensitized by 9, 10-dicyanoanthracene (DCA) and
lumiflavin (LF) to give similar, oppositely-positioned enol derivatives (180, 181)
(Scheme 1.54). Both steroids showed the same reaction pattern associated with the
endocyclic 5- and 4-olefin units, respectively. The reaction was proposed to proceed
via the ene reaction of singlet oxygen and subsequent rearrangement of the initially
formed 5α-hydroperoxides.157
52
RO
RO RO
DCA or LF
hv /O2 OOHOOH
(179) (180)(181)
C8H17
R= H, CH3, CH3CO
or
C8H17
OR
(179a)
R= H, CH3
Scheme 1.54
photosensitized oxygenation of 3-hydroxyflavones 182a, and 182b in the presence of
rose bengal, gave corresponding depsides 183a, and 183b, carbon monoxide, and
carbon dioxide158
(Scheme 1.55).
53
O
R
RR
R
OR'
O
(182a), R=OMe, R'= H(182b), R= R'= H
O
R
RR
R
O
O
HOO
hv, O2
O
R
RR
R OHO
O
O O
O
R
RR
R
O
R
RR
R
CO-COOH
O
O
R
RR
RCOOH
OH
OO
O
- CO2(or-CO)
-CO
(183a), R= OMe(183b), R= H
Rose bengal
Scheme 1.55
Photooxidation of 4-amorphen-11-ol (184), one of the major sesquiterpene natural
products from the medicinal plant Fabiana imbricata, results in three allylic
hydroperoxides,159 (185, 186, 187),which are expected from the "ene-type" reaction of
molecular oxygen with the tri-substituted double bond in 184. The tertiary allylic
hydroperoxide 185 undergoes carbon-carbon bond cleavage and a second
autoxidation reaction to yield the more highly oxygenated seco-amorphane 188 under
very mild conditions (Scheme 1.56).
54
OH OH
hv/O2
(184) (185) (186)
H
methyleneblue
H
6
CDCl3autooxidationat C-6
OH
O
HO
HOO
(188)
+
H
H
OH
HOO
+
H
HHOO
OH
(187)
Scheme 1.56
The key step in the synthesis of spongianolide A (190), an antitumoral natural
sesquiterpenoid, involved the photooxygenation of trimethylsilylfuran160 (189) as
shown in Scheme (1.57).
OO
H
H
OO
H
H
OAC
H
H
O2,TPP,hv, CH2Cl2
-780 C,30 min
O
TMS
(189)
O
O
OH
(190)
O
O
OH
Scheme 1.57
55
A Stereoselective synthesis of zoanthamine (191), potent anti-inflammatory alkaloid,
was accomplished by a strategy involving photosensitized oxidation of furan
derivative in the key step161
(Scheme 1.58).
O
O
OAcTMS
O
OAcCHOOMe
O
N
O
O
R
H
H
O
H
OO
(191)
1. 3O2, hv.00C
RB, CH2Cl2
2. salt. NH4Cl aq3. TMSCHN2
CH2Cl2-MeOH
Scheme 1.58
Sometimes dioxetanes are primarily detected as photooxygenation adducts in the
reaction of benzofurans,162
naphtofurans, naphtodifurans163
and furonaphthopyrones
(192), which finally leads to characteristic cleavage products (Scheme 1.59). An
anomalous behaviour has been observed in the photooxygenation of furanopyrone
(193). Indeed differently from 192 which give the corresponding dicarbonyl
56
compound, 193 lead to stable hydroperoxide (194) by an ene-type reaction164
(Scheme
1.60).
OO O
CH3
H3C
O O
CH3
O
O
H3C
CHO
O2, TPP, hv
(192)
Scheme 1.59
O2, TPP, hvO O
H3C
H3C
H3C O
O O
H3C
H2C
H3C O
HOO
(193) (194)
Scheme 1.60
The most significant application of the photooxygenation of indole derivatives is in
the synthesis of alkaloids.165 The photooxygenation of 1,2,3,4-tetrahydrocarbazole is
the starting step in the synthesis of spiro derivatives, which would be used as a
starting material for the synthesis of spiro analogues of the ergot alkaloid (Scheme
1.61).
NH
N N NH
OHOO HO3O2, hv,
polymer supported RB
NaSO3/H2O
10%
H2SO4/H2O
10%
Scheme 1.61
57
The photooxidative double bond cleavage has been usefully adopted for the
construction of large heterocyclic rings containing a carbonyl group. Utilizing this
type of reaction the quinine alkaloid campthothecin has been synthesized by quinoline
obtained via photooxygenation of indole (195) followed by the basic treatment of the
resulting keto-amide (196) (Scheme 1.62).166
NH
N
O
Me
H
COOMe
O
COOBu
HN
N
O
O
O
H
COOMe
O
COOB uMe
1O2
(195) (196)
Scheme 1.62
Tryptophan (197) on reaction with oxygen molecule in the presence of riboflavin or
methylene blue as a photosensitizer yields N-formylkynurenine (198) and its
derivative.167,168 The hydroxide (199) has also been found by reduction of the crude
oxygenation mixture, it gives oxytryptophan (200) under acidic conditions169
(Scheme
1.63).
58
NH
NH2
H
COOH
NH
NH2
COOH
HOO
NHCHO
NH2
COOH
O
NH
NH
HOCOOH
H
NH
NH
HOOCOOH
H
NH
NH2
COOH
O
H
HCl
1O2, Me2S
(197)
(200)
(198)
(199)
1O2
Scheme 1.63
The variety in molecular structure of the phototoxic drugs is immense, and almost all
classes of drug compounds contain members with adverse photobiological effects. A
knowledge of the part of the molecular structure which is responsible for the
phototoxicity of a particular drug can provide the opportunity to alter a phototoxicon
in such a way that the adverse photobiological effects diminish while the desired ones
remain conserved. This aim can be reached more efficiently by combining
photoreactivity data from both in vitro and in vivo investigations. The in vivo system
is too complicated and without continuous help from in vitro research, the
investigation of this cannot provide much insight. Therefore, we have carried out in
vitro photochemical studies on certain synthetic drugs and biologically active natural
products, as described in the following chapters.
59
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