RECERCA EN PRODUCTES NATURALS Amaryllidaceae com a …diposit.ub.edu/dspace/bitstream/2445/102073/1/Seminari recerca... · RECERCA EN PRODUCTES NATURALS Dr. Laura Torras Claveria;

RECERCA EN PRODUCTES NATURALS

Dr. Laura Torras Claveria; Luciana Tallini, Dr. Francesc

Viladomat, Dr. JaumeBastida

Seminarisde Recercade la Facultatde Farmcia

27 de setembrede 2016

Plantes ornamentals de la famlia Amaryllidaceaecom a font de

compostos bioactius

Hymenocallis littoralis

Phaedranasadubia

Crinum x powellii

Galanthus nivalis

Lycoris radiata

Narcissuscv. Pinza

AMARYLLIDACEAE

1981-2010

Newman & Cragg, J Nat Prod 2007, 70, 461-477

Newman & Cragg, J Nat Prod 2012, 75, 311-335

Natural Products

All newapproveddrugs

Natural product and/or natural product structures play a highly significant role in the drug discovery and development

New drugs Pre-clinic Clinic assays (Phases I-III)FDA Revision

Production/ Phase IV

5 Years 1,5 Years 6 Years 2 Years 2 Years

Pre

sen

taci

n

ND

A

Pre

sen

taci

n

IN

D

5 compounds

Average time in each step

250 compunds

IND: InvestigationalNew Drug

NDA: New DrugApplication

Research and development

of new products

1 approved drugFDA

10.000compounds

AmaryllidaceaefamilyBulbous plant family with ornamental and medical value

3 subfamilies: Agapanthoideae, Allioideae, and Amaryllidoideae(previously 3 families)

Term Amaryllidaceae

corresponds with subfamily Amaryllidoideae

Hippocrates of Kos (460-370 BC). Narcissus oil

Uterus tumors

Dioscorides(40-90 AD)Soranusof Ephesus (98-138 AD)

Same therapy

Pliny the Elder (23-79 AD)Topic use

Narcissus extracts

BibleNarcissus tazetta

Anti-tumor therapy

Middle AgesChinese medicine, N Africa

Narcissus oil

European doctorsHymenocalliscaribaeatumors inflammation

Amaryllidaceaemedical uses through History

Amaryllidaceaegeographical distribution

Amaryllidaceae: Africa

Amaryllidaceae: America

Hymenocalliscoronaria(Alabama)

Amaryllidaceae: Asia

Amaryllidaceae: EuropeMediterranean area

Caucasus

Narcissus poeticus(Vall , Catalonia)

Amaryllidaceaealkaloids

6

4a

1

4a

10b10a

10

9

8

7 6

12

11

4

3

2

norbelladine lycorine homolycorine

crinine narciclasinehaemanthamine

tazettine

montanine

6a'

43

2

16

5

1'2'

3'

4' 6'5'

12 11

3

21

4

4a

10b10a

6a7

109

8

12

3

4

4a10b

10a

6a 6

10

9

87

1

11

12

32

66a

10a10

7

8

910b

4

7 6

11

4

1

2

10b

4a

10a

6a

3

8

910

1

4

4a12

11

6

6a7

10

8

911a 2

3

10a

1210a

6a7

8

910

11 12

1

23

4

4a

10b

6

galanthamine

NH

HO

HO

HO

N

O

O

OH

HO

H

H

O

MeN

MeO

MeO

H

H

O

H

NH

OH

O

O

O

NMe

OMe

H

OH

O

O

4a

1

11

12

32

66a

10a10

7

8

910b

4

NH

OMe

O

O

OH

NH

OH

OH

OH

H

OH O

O

O

N

OMe

OHO

O H

O

NMe

MeO

OH

Other Amaryllidaceaealkaloids

O

NMeO

O

4a

10b

GracilineEsqueleto dibenzo[b,d]piranoConfiguracin absoluta 4aR/10bR

RR

Galanthus gracilisGalanthus plicatus ssp byzantinusPancratium maritimum

N

NMeO

O

OMe

H

O

O

OH

H

PlicamineCompuesto dinitrogenado no dimricoCentro spiro = Tazettina [O/N]

Galanthus plicatus ssp byzantinusCyrthantus obliquus

Graciline Plicamine

Dibenzo[b,d] piranskeletonAbsolute configuration 4aR/10bR

GalanthusgracilisGalanthusplicatusssp. ByzantinusPancratiummaritimum

Non dimeric dinitrogenatedcompoundSpiro center = Tazettine[O/N]

Galanthusplicatusssp. ByzantinusCyrthantusobliquusNarcissus broussonetii

Exceptions

NMe

O

O

O

O

O

H

H O

NMe

O

OH

HO

MeO

NMe2

ONMe2

O NMe

OMe

O

OMe

NMe

OMe

OH

OMe

(-)-capnoidineFumariaceae

(+)-bulbocapninePapaveraceae, Fumariaceae yLauraceae

amisineAizoaceaeHymenocallis arenicolaZ Chem 1980, 20: 298

mesembrenolAizoaceaeCrinum oliganthumZ Chem 1981, 21: 358

mesembrenoneAizoaceaeNarcissus pallidulusJ Nat Prod 1989, 52: 478

NH

HO

MeO

salsolineChenopodiaceae (Salsola richteri)Galanthus woronowii

Me

Galanthus nivalis ssp cilicicusBiochem Syst Ecol 2004, 32, 1059

Biochem Syst Ecol 2013, 51, 276

Chemotaxonomic value

O

NMe

O

NMe

COO

NMe

COOH

Shihunine

Dehidroshihunine

H

BehriatenuifloraGreene

Amaryllidaceae AlliaceaeBastida, Sells, Codina, Viladomat, Len de la LuzPlanta Medica 1996, 62, 575-577

Amaryllidaceaealkaloids biosynthesis

trans-cinnamic acid, R1=R2=Hpara-coumaric acid, R1=OH, R2=Hcaffeic acid, R1=R2=OH

tyramine

Tyr-decarboxylase

protocatechuic aldehyde

PAL

L-TyrL-Phe

HO

H2N COOH

HO

H2N

COOH

R1

R2 CHO

HO

HO

NH2

COOH

1.- Enzimaticpreparation of precursors

-oxidation

PAL

hydroxylases

reduction

Tyr-decarboxylase

CHO

HO

HO

HO

H2N

N

HO

HONH

HO

O

H

N

HOHOHO

HO

OH

H

NH

HO

HO

HO

tyramineprotocatechuic aldehyde

Schiff's base(isomeric structures in solution)

norbelladine

Amaryllidaceaealkaloids biosynthesis2.- Primary ciclation


3.- Enzimaticpreparation of intermediary agents

MeO

NHHO

4'

HO

HO

NHHO

4'

HO

norbelladine O-methylnorbelladine


4.- Secondary ciclation. Diversification

types

galanthamine

types

crinine haemanthaminetazettinenarciclasinemontanine

types

lycorinehomolycorine

ortho-para' para-para' para-ortho'

O-methylnorbelladine

MeO

NHHO

4'

HO



types

galanthamine

types


types




MeO

NHHO

OH



types

galanthamine

types


types




MeO

NH

OHOH

Natural Products Research

SCREENING STRUCTURAL CHARACTERIZATION

Studyof genusNarcissus

[Spain-Portugal]

Studyof Amaryllidaceae

spp. usedin TradMed[SA/Ibero-America]

Studyof galanthamine

producerspecies[Chemotaxonomy]

Catalan flora

19831980 20111993 2005I II III

Phytochemical screening

SCREENING

Catalan flora

19831980

Collection, Drying, StorageTaxonomic DeterminationObtaining genus informationSimple method rapid selection

NarcissusassoanusDuf.=N. requieniiRoem.

=N. juncifoliusLag.

(Amaryllidaceae)

> 1000 samples Green plants & Fungus

different habitats from Catalonia




[Spain-Portugal]





Catalan flora

19831980 20111993 2005I II III

Selection of genus Narcissus

High content in exclusive AmaryllidaceaealkaloidsBiological and pharmacological activity of extracts and alkaloids previously isolated from this family speciesPoor studied genusInfluence area: Mediterranean (easy to work)

In base of:

Selection of genus Narcissus

Distribution South Europe (Iberian Peninsula and Italy) (also in North Africa and East Mediterranean)

80-100 speciesNarko(=narcotic) penetrating smell of flowers from some speciesGrowing from lowlands to highlandsFlowering at the end of winter - spring

*

*

**

Plant material

Extracts FractionsPure

compounds

SpectroscopyUV, IR, MS,

NMR (1D/2D), X Ray

Structure elucidation

Methodology

Alkaloids from genus Narcissus

N

OH

HO

O

OH

H

12

3

4

4a

6

11

12

7

10 10b

6a8

9 10a

Lycorine, NarcissuspseudonarcissusGerrad, 1877: isolationNagakawaet al., 1956: characterization

New alkaloids from Narcissus

N

HO

MeO

H

H

OR2

R1O

1-O-acetylpseudolycorine R1= Ac, R2= H2-O-acetylpseudolycorine R1= H, R2= Ac

N

MeO

MeO

oxoassoanine

O

O

R1O

R2O

MeN

H

H

O

9

9-O-demethylhomolycorine R1=H, R2= Me, R3= Hdubiusine R1= COCH2CHOHMe, R2= Me, R3= OAc9-O-demethyl-2 -hydroxyhomolycorine R1= H, R2= Me, R3= OH8-O-acetylhomolycorine R1= Me, R2= Ac, R3= H

H

NMe

O

O

bicolorine

R3

N

MeO

MeO

vasconine R= Htortuosine R= OMe

N

MeO

MeO

OMe

roserine

O

R1O

R2O

MeN

H

H9

H

OMe

O-methyllycorenine R1=R2= Me, R3=H2 -hydroxy-6-O-methyloduline R1+R2= CH2, R3=OH

R3

R

New alkaloids from Narcissus

OMeO

OH

N

H

O

N-formylnorgalanthamine

N

OH

HO

MeO

9

H

9-O-demethylmartidine

OMeO

NH

epinorgalanthamine

OMeO

NH

epinorlycoramine

OH OH

N

OAc

HO

MeO

9

H

cantabricine

N

OMe

H

11-O-acetylhaemanthamine

N

OMe

H

bujeine

OAcO

O

O

O

MeCOOCH2

O

nangustine

O

O N H OH

OH

O

NH

HO H

O

O

obesine

O

NMeO

O

OMe

OOMe

N

HO

pallidiflorine

11

Bastida, Lavilla, Viladomat. TheAlkaloids2006, 63, 87-179




[Spain-Portugal]





Catalan flora

19831980 20111993 2005I II III

Amaryllidaceaein traditional medicine

KwaZulu-Natal200.000 Traditionalhealers(Year2004 licencesauthorization) South Africa


Brunsvigia

B. josephinaeB. orientalisB. radulosaB. littoralisB. bosmeniae

CrinumC. sthulmaniiC. kirkiiC. delagoenseC. macowanii

CyrtanthusC. elatusC.sanguineusC. obliquus

Nerine

N. filifolia

stomach painLeprosy affected areas

pregnancy (facilitate birth)

sexually transmitted diseases (STD)lactation

urinary problems

South Africa


AmmocharisA. tinneana

BoophaneB. flava

Used by indigenous population (Xhosa, Shoto, San, Zulu ...) Infusions of bulbs [> 200 years]. A lot of species from genus Boophane, Brunsvigia, Crinum andNerineare used to treat infertility

South Africa

Plant material

Extracts FractionsPure

compounds

Biological assays

Mass spectrometryGC-MS, LC-MS

SpectroscopyUV, IR, MS,

NMR (1D/2D), X Ray

Structure elucidation

Methodology


South Africa

N

OH

H

MeO

HO

N

OAc

OH

R1

R2

H

N

O

O

OH

OMe

OMe

HN

O

O

OH

OMe

OMe

H

N

OR2

R1O

R3

O

OH

N

O

O

OAc

HO

H

N

O

O

OMe

AcO

OMe

HN

O

O

OMe

O

OMe

H

N

O

O

O NH

OOR1

OHOMe

josephinine

11-O-acetylambelline

brunsbelline

1-epibowdensine R1= R2= Ac, R3= OMe1-epidemethoxybowdensine R1= R2= Ac, R3= H1-epideacetylbowdensine R1= R2 =H, R3= OMe

1

delagoensine R1+R2= OCH2Odelagoenine R1= R2= OMe

6 -hydroxycrinamidine R= H6 -hydroxyundulatine R= Me

macowiine 6 -hydroxybuphanidrine

filifoline

OH


South Africa

N

MeO

HO

H

H

HO

NH

H

AcO

O

O

OAc

O

O

O

HN

O

N

NMeO

O

OMe

O

H

H

OH

N

O

O

OMe

OH

NMe

MeO

RO

N

MeO

HO

H

H

AcO

NH

MeO

MeO

MeO

O

O

O

N

O

kirkine

buflavine R= Me8-O-demethylbuflavine R= H

8

montabuphine

1-O-acetylnorpluviine

obliquine

1,2-O-diacetylzephyranthine

noraugustamine 4a-dedihydronoraugustamine

N-demethylbelladine

Amaryllidaceaein Ibero-America


Ibero-America

N

O

O

O N

MeO

MeO

O

H

N

MeO

MeO

OMe O

NH

O

O

O

O

NMeO

O

OMe

OMe

H

H

ungeremine oxomaritidine

7-methoxyassoanine

apohaemanthamine

6-O-methylpretazettine

MeO

O

NMe

OH

OH

11 -hydroxygalanthamine

Andrade, Berkov, Viladomat, Codina, Zuanazzi, BastidaMolecules2011,16, 7097-7104 (11 -hydroxygalanthamine)

Amaryllidaceaemicropropagation

Ibero-America

Study of species in danger of extinctionStudy of insufficient samples




[Spain-Portugal]





Catalan flora

19831980 20111993 2005I II III

Galanthamine

Galanthamine

H3CO

NCH3

O

OH Acetylcholinesteraseinhibitory activity

Interaction with nicotinic receptors

Commercialized for the treatment of mild to

Geographic study Leucojumaestivum

Distribution of different alkaloid types in Leucojumaestivumpopulations in Bulgaria

Berkov, Georgieva, Kondakova, Viladomat, Bastida, Atanassov, CodinaBiochemical Systematics in Ecology 2013, 46, 152-161

Methodology: GC-MS

software AMDISAutomaticMassSpectralDeconvolutionand IdentificationSystem

Separationand identificationof Amaryllidaceaealkaloids in complex mixtures and extracts without derivatisating

Structural information of new compounds

Differentiation of coelutingcompounds

Methodology: GC-MS

software AMDISAutomaticMassSpectralDeconvolutionand IdentificationSystem

Identification of Amaryllidaceaealkaloids

Amaryllidaceaealkaloids library NIST databaseLiterature

KovatsRetention IndexMass spectra

Methodology: GC-MSsoftware AMDIS

GAL in ornamental Narcissus

105 ornamental Narcissuscultivars were evaluated in terms of GAL content and AChEinhibitory activity, as a new source of GAL for pharmaceutical industry

Torras-Claveria, Berkov, Codina, Viladomat, Bastida Industrial Cropsand Products, 2013, 43, 237-244

Narcissus hispanicus




Bulbs and leaves were evaluated separately


GAL contentGC-MS

AChEinhibitory activity

In vitro test

GAL content


0

1000

2000

3000

4000

5000

6000

7000

8000

N. confusus N. hispanicusYellow WingsRijnveld EarlySensation

Rip VanWinkle

g

Ga

l /g

DW

Galanthamine

content in

leaves

0

2000

4000

6000

8000

10000

12000

14000

16000

N. confususYellow WingsBella Estrella Enkele JonquillaSimplex

N. hispanicus

g

Ga

l/g D

W

Galanthamine

content in

bulbs

AchEinhibitory activity


0,000

0,200

0,400

0,600

0,800

1,000

1,200

Snowball GreenHoward

N. confusus Hawera Albus PlenusOdoratus

PinkParadise

N. hispanicus

AC

hEi

nh

ib. A

ct.(

IC50)

0,000

0,200

0,400

0,600

0,800

1,000

1,200

N. confusus Hawera Little Spell

AC

hEi

nh

ib. A

ct.

(IC

50)

IC 50

AChE

inhibition

in leaves

IC 50

AChE

inhibition

in bulbs

AchEinhibitory activity


Galanthaminecontent

AChEactivity inhibition

N. hispanicus

Cluster analysis Clustering, the organization of a collection of patterns based on similarity. Its aim to find structure in data

LEAFsamples

ALKALOID PROFILE

BULBsamples

5 clusters

5 clusters


Hierarchical cluster

RupSud Vel

LEAFsamples

BULBsamples


Lycorine type

0,00

500,00

1000,00

1500,00

2000,00

2500,00

3000,00

D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13

g

GA

L/D

W

Horticultural divisions

Galanthamine type

Haemanthamine type

Homolycorine type

Lycorine type

Narciclasine type

Tazettine type

Other

Protoalkaloids

LEAFsamples Horticultural divisions

Galanthamine type

0,00

500,00

1000,00

1500,00

2000,00

2500,00

3000,00

D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13

g

GA

L/D

W

Horticultural divisions

Galanthamine type

Haemanthamine type

Homolycorine type

Lycorine type

Narciclasine type

Tazettine type

Other

Protoalkaloids

BULBsamples Horticultural divisions

Statistical analysis

Correspondence analysis

C1 C2 C3 C4 C5 All

D1 0 7 1 8 0 16

D2 0 4 0 9 0 13

D3 0 3 0 9 0 12

D4 0 4 0 8 0 12

D5 0 2 0 5 0 7

D6 0 7 2 6 0 15

D7 0 2 0 6 0 8

D8 0 0 1 0 0 1

D9 0 2 0 0 0 2

D10 0 1 0 2 0 3

D11 0 3 0 3 0 6

D12 0 2 0 0 0 2

D13 1 1 2 4 1 9

All 1 38 6 60 1 106

C1 C2 C3 C4 C5 All

D1 4 2 3 7 0 16

D2 2 3 3 5 0 13

D3 2 5 3 2 0 12

D4 7 1 3 1 0 12

D5 1 0 6 0 0 7

D6 6 6 2 1 0 15

D7 2 1 3 2 0 8

D8 0 0 1 0 0 1

D9 0 1 0 1 0 2

D10 0 0 3 0 0 3

D11 1 0 1 4 0 6

D12 0 1 0 1 0 2

D13 2 0 2 4 1 9

All 1 38 6 60 1 106

Cross tabulation



Metabolomics

Ibero-America

Lycoris

2011 - today

Metabolomics

Torras-Claveria, Berkov, Juregui, Caujap, Viladomat, Codina, Bastida Phytochemicalanalysis, 2010, 21, 80-88

Pancratiumcanariense

Pigni, Berkov, Ros-Ruiz, Luque, Viladomat, Codina, Bastida Phytochemistry, 2013, 95, 384-393

Narcissus SectionGanymedes

Torras-Claveria, Berkov, Codina, Viladomat, BastidaIndustrial CropsandProducts, 2014, 56, 211-222

OrnamentalNarcissus varieties and cultivars

Metabolomics

Parejo, Juregui, Viladomat, Bastida, Codina. RapidCommunications in MassSpectrometry, 2004, 18, 2801-2810

Polyphenols LC-MS/MS and LC high resolution MS2000 - today

Snchez-Rabaneda, Juregui, Lamuela-Ravents, Bastida, Viladomat, Codina. Journalof ChromatographyA, 2003, 1008, 57-72

Snchez-Rabaneda, Juregui, Lamuela-Ravents, Viladomat, Bastida, Codina. RapidCommunications in MassSpectrometry, 2004, 18, 553-563

Artichoke waste

Apple pomace

Tagetesmaxima

Torras-Claveria, Juregui, Bastida, Codina, Viladomat. Journalof AgriculturalandFoodChemistry, 2007, 55, 8436-8443

Lavandin

Metabolomics

Luna, Pigni, Torras-Claveria, Monferran, Maestri, Wunderlin, Ferensin, Bastida, Tapia. Journalof FoodCompositionandAnalysis, 2013, 31, 120-128

Polyphenols LC-MS/MS and LC high resolution MS2000 - today

Torras-Claveria, Juregui, Codina, Tiburcio, Bastida, Viladomat. Plant Science, 2012, 182, 71-78

Gasca, Cabezas, Torras, Bastida, Codina. FreeRadicals andAntioxidants, 2013, 3, S55-S61

Tobacco

Pavoniasepioides

Ramorinoagirolae

De Andrade, Berkov, Viladomat, Codina, Zuanazzi, Bastida. Molecules, 2011, 16, 7097-7104

Hippeastrumpapilio

De Andrade, Pigni, Torras-Claveria, Guo, Berkov, Reyes-Chilpa, El Amrani, Zuanazzi, Codina, Viladomat, Bastida. Revista Latinoamericanade Qumica, 2012, 40, 83-98

GenusHippeastrum

De Andrade, Guo, Font-Bardia, Clavet, Dutilh, Viladomat, Codina, Nair, Zuanazzi, Bastida. Phytochemistry, 2014, 56, 188-195

Hippeastrumaulicumand calyptratum

Guo, de Andrade, Pigni, Torras-Claveria, Tallini, Borges, Viladomat, Nair, Zuanazzi, Bastida. HelveticaChimicaActa, 2016, 99, 143-147

Sebben, Giordani, de Andrade, Berkov, Osorio, Sobral, de Almeida, Henriques, Bastida, Zuanazzi. Revista Brasileirade Farmacognosia, 2015, 25, 353-355

Hippeastrumbreviflorum

Reyes-Chilpa, Berkov, Hernndez-Ortega, Jankowski, Arseneau, Clotet-Codina, Est, Codina, Viladomat, Bastida. Molecules, 2011, 16, 9250-9533

Zephyranthesconcolor

Osorio, Berkov, Brun, Guo, Codina, Viladomat, Cabezas, Bastida. PhytochemistryLetters, 2010, 3, 161-163

Phaedranassadubia

De Andrade, Giordani, Torras-Claveria, Pigni, Berkov, Font-Bardia, Calvet, Konrath, Bueno, Sachett, Dutilh, Borges, Viladomat, Henriques, Nair, Zuanazzin, BastidaPhytochemistryReviews, 2016, 15, 147-160

Brazilian Amaryllidaceaeas a source of acetylcholinesterase inhibitory alakaloids

Guo, Pigni, Zheng, de Andrade, Torras-Claveria, Borges, Viladomat, Codina, BastidaNatural ProductCommunication, 2014, 9, 1081-1086

Bioactive alkaloids in Lycorisspecies

Pharmacological activity

Increase of interest in pharmacological activity of Amaryllidaceaealkaloids since GAL approval by FDA

Anti-tumoralAnti-parasiticAcetylcholinesterase inhibitionDocking studies


Some Amaryllidaceaehave been historically used in symptomatologiesidentified as cancer

Citotoxicitytest in anti-tumor compounds

Toxicity test in ArtemiasalinaPrevious evaluation of AmaryllidaceaecompoundsReproducible and comparable values



Evaluation in 60 cell lines




Apoptosis Selectivity

NH

O

O

OH

OH

HO

OH

OH O

Pancratistatin

McLachlan, Kekre, McNulty, Pandey. Apoptosis2005, 10, 619-630Kekre, Griffin, McNulty, Pandey. CancerChemother. & Pharmacol. 2005, 56, 29-38

Selective apoptosis of tumoral cellsMinimal effects in normal cellsEarly activation of Caspasa-3Fast apoptosis in Human Linfomacells


Apoptosis SAR studies Selectivity Hepatoma (5123tc)

N

O

O

OH

HO

HN

O

O

OAc

HO

HN

O

O

H

OH

N

O

O

H

OMe

OMe

HO

N

O

O

H

OH

OMe

N

O

O

H

OH

OMe

N

O

O

HN

O

O

H

HO

OMeO

OMe MeO

OOMe

OH

amabiline(3)

josephinine(4)

crinine(5)

ambelline(6)

crinamine(7)

haemanthamine(8)

epoxyambelline(9)

6 -hydroxyundulatine(10)

25mM 48h treatment

0

10

20

30

40

50

60

70

80

90

100

C A1 A2 A3 A4 A5 A7 A8 A10

% A

po

pto

tic

c 3 4 5 7 8 6 9 10

C 3 4 5 7 8 6 9 10

McNulty, Nair, Codina, Bastida, Pandey, Gerasimoff, Griffin. Phytochemistry2007, 68, 1068-1074

% A

po

pto

sis

CRININE-HAEMANTHAMINE


Apoptosis SAR studies Selectivity Hepatoma (5123tc)

McNulty, Nair, Codina, Bastida, Pandey, Gerasimoff, Griffin. Phytochemistry2007, 68, 1068-1074

Pharmacophoricrequirements

Presence of ethanobridge -5,10bMethoxylgroup tolerance in or in C-3Hydroxyl group in position 11

N

OHO

O

OMe311

H


Anti-parasitic

Parasite Disease Infectectedpeople Detection

Plasmodiumfalciparum

Malaria 300 millions (2 millions death/year)

HypoxanthineH3 incorporation

Leishmaniasp. Leishmaniasis 12 millions Microscopy

Trypanosoma brucei-rhodesiense

Sleeping sickness 300.000(100%mortality)

Alamarblue assay (colorimetry)

Trypanosoma cruzi Chagas disease 18 milions Colorimetry

Spencer et al., Lloydia1947, 10, 145-174

Pharmacological activityAnti-parasitic

Parasite: strain: stage: reference drug:

T. b. rhodesiense STIB 900 trypomastigotes Melarsoprol

T. cruzi Tulahuen C4 amastigotes Benznidazole

L. donovani MHOM-ET-67/L82 amastigotes Miltefosine

P. falciparum K1 IEF Chloroquine

Cytotoxicity L6 Podophyllotoxin All values as: g / mL

ID No IC-50 ref drug IC-50 ref drug IC-50 ref drug IC-50 ref drug IC-50 ref drug

Ungeremine 0,979 0,003 0,85 0,22 >30 0,17 0,0933 0,0321 17,3 0,008

Buphanamine 28,75 0,003 >30 0,22 >30 0,17 4,31 0,046 >90 0,008

Zefbetaine 39,22 0,003 >30 0,22 >30 0,17 >5 0,046 >90 0,008

Galanthamine 37,92 0,003 >30 0,22 >30 0,17 >5 0,046 >90 0,008

Pdub Extract 27,43 0,003 >30 0,22 >30 0,17 >5 0,046 >90 0,008

P. falc. K1 Cytotox. L6T.b.rhod. T. cruzi L.don. axen.

N

R1O

R2O

O

OMeO

NMeN

HO

O

O

OMe

H

OH

Buphanamine GalanthamineUngeremine: R1+R2=CH2Zefbetaine: R1=R2=Me

Osorio, Robledo, Bastida. TheAlkaloids2008, 66, 113-190


Strategy to palliate Alzheimer symptomatology

Acetylcholinesterase activity inhibition

Drugs with cholinergic activity

H3CO

NCH3

O

OH

Ellmanin vitro assay to test Amaryllidaceaealkaloids and plant extracts

Galanthamine

Documents

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