RESUMO
In our continuing search for novel natural products with antiplasmodial activity, an extract of Aniba citrifolia was found to have good activity, with an IC50 value less than 1.25 µg/mL. After bioassay-directed fractionation, the known indolizinium alkaloid anibamine (1) and the new indolizinium alkaloid anibamine B (2) were isolated as the major bioactive constituents, with antiplasmodial IC50 values of 0.170 and 0.244 µM against the drug-resistant Dd2 strain of Plasmodium falciparum. The new coumarin anibomarin A (3), the new norneolignan anibignan A (5), and six known neolignans (7-12) were also obtained. The structures of all the isolated compounds were determined based on analyses of 1D and 2D NMR spectroscopic and mass spectrometric data, and the absolute configuration of anibignan A (5) was assigned from its ECD spectrum. Evaluation of a library of 28 anibamine analogues (13-40) indicated that quaternary charged analogues had IC50 values as low as 58 nM, while uncharged analogues were inactive or significantly less active. Assessment of the potential effects of anibamine and its analogues on the intraerythrocytic stages and morphological development of P. falciparum revealed substantial activity against ring stages for compounds with two C-10 side chains, while those with only one C-10 side chain exhibited substantial activity against trophozoite stages, suggesting different mechanisms of action.
Assuntos
Alcaloides/farmacologia , Antimaláricos/farmacologia , Lauraceae/química , Plasmodium falciparum/efeitos dos fármacos , Piridinas/farmacologia , Linhagem Celular Tumoral , Guiana , Humanos , Estrutura Molecular , Compostos Fitoquímicos/farmacologiaRESUMO
Natural products continue to provide a diverse and unique source of bioactive lead compounds for drug discovery, but maintaining their continued eminence as source compounds is challenging in the face of the changing face of the pharmaceutical industry and the changing nature of biodiversity prospecting brought about by the Convention on Biological Diversity. This review provides an overview of some of these challenges and suggests ways in which they can be addressed so that natural products research can remain a viable and productive route to drug discovery. Results from International Cooperative Biodiversity Groups (ICBGs) working in Madagascar, Panama, and Suriname are used as examples of what can be achieved when biodiversity conservation is linked to drug discovery.
Assuntos
Biodiversidade , Produtos Biológicos , Descoberta de Drogas , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Indústria Farmacêutica , Madagáscar , Estrutura Molecular , Panamá , SurinameRESUMO
The approach to new drugs through natural products has proved to be the single most successful strategy for the discovery of new drugs, but in recent years its use has been deemphasized by many pharmaceutical companies in favor of approaches based on combinatorial chemistry and genomics, among others.Drug discovery from natural sources requires continued access to plant, marine, and microbial biomass, and so the preservation of tropical rainforests is an important part of our drug discovery program. Sadly, many of the tropical forests of the world are under severe environmental pressure, and deforestation is a serious problem in most tropical countries. One way to combat this loss is to demonstrate their value as potential sources of new pharmaceutical or agrochemical products.As part of an effort to integrate biodiversity conservation and drug discovery with economic development, we initiated an International Cooperative biodiversity Group (ICBG) to discover potential pharmaceuticals from the plant biodiversity of Suriname and Madagascar. The Group, established with funding from agencies of the United States government, involved participants from the USA, Suriname, and Madagascar. The basic approach was to search for bioactive plants in the Suriname and Malagasy flora, and to isolate their bioactive constituents by the best available methods, but the work included capacity building as well as research. Progress on this project will be reported, drawing on results obtained from the isolation of bioactive natural products from Suriname and Madagascar. The benefits of this general approach to biodiversity and drug discovery will also be discussed.
RESUMO
7-(2'-Hydroxy-3'-chloroprenyloxy)-4,8-dimethoxyfuroquinoline (1) and 6-(2'-hydroxy-3'-chloroprenyloxy)-4,7-dimethoxyfuroquinoline (2), together with ten known compounds, have been isolated from the aerial parts of Ertela (Monnieria) trifolia (L.) Kuntze. All the isolates were tested for antiproliferative activity against the A2780 human ovarian cancer cell line.
Assuntos
Alcaloides/química , Quinolinas/química , Rutaceae/química , Clima Tropical , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neoplasias Ovarianas/patologia , Quinolinas/farmacologia , Chuva , SurinameRESUMO
A new cytotoxic macrocyclic glycoresin, ipomoeassin F (6), has been isolated from the leaves of Ipomoea squamosa. The structure was elucidated by the interpretation of spectral data. Compound 6 was strongly active in the A2780 (human ovarian cancer cell line) assay with an IC(50) value of 0.036 microM.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Glicoconjugados/administração & dosagem , Glicoconjugados/química , Glicoconjugados/farmacologia , Glicoconjugados/uso terapêutico , Ipomoea , Fitoterapia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta , SurinameRESUMO
Bioassay-guided fractionation of the MeOH and EtOAc fractions of extracts of two lianas collected in Suriname has led to the isolation of five new diterpenoids, humirianthone 1, 1-hydroxy-humirianthone 2, 15R-humirianthol 3, patagonol 4, and patagonal 5, and the five known diterpenoids, humirianthol 7, annonalide 8, acrenol 9, icacinol 10, and the oxidized annonalide 11. All 10 diterpenoids showed cytotoxic activity against the A2780 human ovarian cancer cell line, and compounds 1, 3, 8, and 9 also showed activity against phytopathogenic fungi.
Assuntos
Diterpenos/isolamento & purificação , Diterpenos/toxicidade , Plantas Medicinais/química , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos/farmacologia , Fungos/efeitos dos fármacos , Fungos/fisiologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Chuva , Suriname , ÁrvoresRESUMO
The new glycoresins, ipomoeassins A-E (1-5), have been isolated from the leaves of Ipomoea squamosa. The structures were elucidated by spectroscopic analyses and chemical transformations. The absolute configurations of C-5 (ipomoeassins 3-5) and C-11 (ipomoeassins 1 and 2) were determined by their derivatives with (R)- and (S)-MPA. All the isolates were active in the A2780 human ovarian cancer cell line assay, and 4 showed the highest activity with an IC(50) value of 35 nM.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Glicosídeos/isolamento & purificação , Ipomoea/química , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Estereoisomerismo , Suriname , Células Tumorais CultivadasRESUMO
Bioassay-guided fractionation of an EtOAc extract of the leaves of Melampodium camphoratum using an assay for inhibitors of the degradation of hemin resulted in the isolation of six new eudesmane sesquiterpenes (1-6) and the known 6-epi-beta-verbesinol coumarate (7). The structures of compounds 1-6 were established as 6alpha-(4'-O-methyl-7'E-coumaryloxy)eudesm-4(14)-ene (1), 6alpha-({4'-O-stearyl}-7'E-coumaryloxy)eudesm-4(14)-ene (2), 6alpha-({4'-O-palmityl}-7'E-coumaryloxy)eudesm-4(14)-ene (3), 6alpha-({4'-O-[9' 'Z-hexadecenoyl]}-7'E-coumaryloxy)eudesm-4(14)-ene (4), 6alpha-(7'Z-coumaryloxy)eudesm-4(14)-ene (5), and 6alpha-({4'-acetoxy}-7'Z-coumaryloxy)eudesm-4(14)-ene (6). Compounds 1-4 showed weak activity in the hemin degradation assay, while compounds 5-7 were inactive.
Assuntos
Antimaláricos/isolamento & purificação , Asteraceae/química , Hemina/metabolismo , Plantas Medicinais/química , Sesquiterpenos de Eudesmano/isolamento & purificação , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Folhas de Planta/química , Plasmodium falciparum/efeitos dos fármacos , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/farmacologia , Estereoisomerismo , SurinameRESUMO
Bioassay-directed fractionation of a methyl ethyl ketone extract of the roots of Endlicheria aff. resulted in the isolation of four new neolignans (1-4) and eight known compounds, namely, canellin A (5), canellin C (6), 3'-methoxyguianin (7), (7S,8R,1'S,5'S,6'R)-Delta(2',8')-3',6'-dihydroxy-5'-methoxy-3,4-methylenedioxy-4'-oxo-8.1',7.5'-neolignan (8), armenin-B (9), dillapiole (10), 1-allyl-2,6-dimethoxy-3,4-methylenedioxybenzene (11), and omega-hydroxyisodillapiole (12). The structures of the new compounds (1-4) were established as (7S,8R,1'S,5'S,6'R)-Delta(2',8')-5',6'-dihydroxy-3'-methoxy-3,4-methylenedioxy-4'-oxo-8.1',7.5'-neolignan, (7S,8R,1'S,5'S,6'R)-Delta(2',8')-3',5',6'-trihydroxy-3,4-methylenedioxy-4'-oxo-8.1',7.5'-neolignan, 2,4-dimethoxy-5,6-methylenedioxy-1-(2-propenyl)benzene, and 2,6-dimethoxy-3,4-methylenedioxycinnamyl alcohol, respectively, on the basis of spectroscopic interpretation.
Assuntos
DNA Polimerase beta/antagonistas & inibidores , Inibidores Enzimáticos/isolamento & purificação , Lauraceae/química , Lignanas/isolamento & purificação , Liases/antagonistas & inibidores , Plantas Medicinais/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lignanas/química , Lignanas/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peru , Raízes de Plantas/química , EstereoisomerismoRESUMO
Bioassay-directed fractionation of a butanone extract of Monochaetum vulcanicum resulted in the isolation of a new triterpene (1) and four known compounds, ursolic acid (2), 2alpha-hydroxyursolic acid (3), 3-(p-coumaroyl)ursolic acid (4), and beta-sitosteryl-beta-d-galactoside (5). The structure of the new compound 1 was established as 3beta-acetoxy-2alpha-hydroxyurs-12-en-28-oic acid on the basis of extensive 1D and 2D NMR spectroscopic interpretation and chemical derivatization. Compounds 1-3 and 5 exhibited polymerase beta lyase activity.
Assuntos
DNA Polimerase beta/antagonistas & inibidores , Inibidores Enzimáticos/isolamento & purificação , Liases/antagonistas & inibidores , Melastomataceae/química , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Acetilação , Costa Rica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Estereoisomerismo , Triterpenos/química , Triterpenos/farmacologia , Ácido UrsólicoRESUMO
Bioassay-directed fractionation of a n-hexane extract of Couepia polyandra using an assay to detect inhibitors of the lyase activity of DNA polymerase beta resulted in the isolation of the new triterpene 3beta,16beta,23-triacetoxyolean-12-en-28-oic acid (1) and four known compounds, oleanolic acid, betulinic acid, stigmasterol, and beta-sitosterol. The structure of the new compound was established on the basis of extensive 1D and 2D NMR spectroscopic interpretation. All five compounds inhibited DNA polymerase beta lyase activity.
Assuntos
Chrysobalanaceae/química , DNA Polimerase beta/antagonistas & inibidores , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Sequência de Bases , Inibidores Enzimáticos/química , Liases/antagonistas & inibidores , México , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Ácido Oleanólico/química , Triterpenos Pentacíclicos , Casca de Planta/química , Caules de Planta/química , Triterpenos/química , Ácido BetulínicoRESUMO
Bioassay-guided fractionation of the EtOAc extract of the twigs of Garcinia macrophylla from Suriname produced the known benzophenone, guttiferone A (1), and a new guttiferone analogue, guttiferone G (2). Friedelin was also isolated. The structures of compounds 1 and 2 were elucidated using 1D and 2D NMR spectroscopy. Compounds 1 and 2 were weakly cytotoxic in the A2780 human ovarian cell line, with IC (50) values of 6.8 and 8.0 microg/mL, respectively.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/farmacologia , Garcinia , Fitoterapia , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Benzofenonas/administração & dosagem , Benzofenonas/química , Benzofenonas/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Neoplasias Ovarianas/prevenção & controle , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , SurinameRESUMO
Two novel triterpene acids, esculentoic acid A ( 1) and B ( 2) as well as the seven known compounds 3 - 9 were isolated from an EtOAc extract of leaves, stems, and twigs of Manihot esculenta by bioassay-guided fractionation for cytotoxic activity. The structures of the two new compounds were established as 3alpha-hydroxytaraxer-14-en-29-oic acid ( 1) and 3-oxotaraxer-14-en-29-oic acid ( 2) on the basis of 1D and 2D NMR spectroscopic data interpretation and chemical conversions. The two new compounds 1 and 2 showed moderate cytotoxicity against the A2780 human ovarian cancer cell line.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Manihot , Fitoterapia , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta , Caules de Planta , Suriname , Triterpenos/química , Triterpenos/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Bioassay-guided fractionation of a CH(2)Cl(2)-MeOH extract of the twigs of Coussarea paniculata using a yeast-based assay for potential DNA-damaging agents resulted in the isolation of three new lupane triterpenoids, 1-3, in addition to eight known triterpenoids, lupeol (4), lupeyl acetate (5), betulin (6), betulinic acid (7), 3-epi-betulinic acid (8), 3-epi-betulinaldehyde (9), oleanolic acid (10), and ursolic acid (11). The structures of the new compounds were established as lup-20(29)-en-3beta,25-diol (1), lup-20(29)-en-11alpha-ol-25,3beta-lactone (2), and 3-deoxybetulonic acid (3), on the basis of extensive 1D and 2D NMR spectroscopic data interpretation and chemical conversion.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Plantas Medicinais/química , Rubiaceae/química , Triterpenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Guiana , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Neoplasias Ovarianas , Caules de Planta/química , Estereoisomerismo , Triterpenos/química , Triterpenos/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Bioassay-guided fractionation of the MeOH extract of Acacia tenuifolia using the engineered yeast strains 1138, 1140, 1353, and Sc7 as the bioassay tool resulted in the isolation of the three new saponins 3, 5, and 6 and the three known saponins 1, 2, and 4. The structures of the new compounds were established on the basis of HRMS, 1D and 2D NMR spectral data on the intact saponins, and GC-MS analyses of the sugars. Compounds 1,2 and 5,6 showed cytotoxicity against mammalian cell lines.
Assuntos
Acacia/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ácido Oleanólico/análogos & derivados , Plantas Medicinais/química , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação , Animais , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares , Camundongos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Neoplasias Ovarianas , Saponinas/química , Saponinas/farmacologia , Estereoisomerismo , Suriname , Triterpenos/química , Triterpenos/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Leveduras/efeitos dos fármacosRESUMO
Bioactivity-directed fractionation of a methanol extract of Hymenaea courbaril afforded the three new diterpenoids (13R)-13-hydroxy-1(10),14-ent-halimadien-18-oic acid (1), (2S,13R)-2,13-dihydroxy-1(10),14-ent-halimadien-18-oic acid (2), and (13R)-2-oxo-13-hydroxy-1(10),14-ent-halimadien-18-oic acid (3). The configurations of these compounds were determined from X-ray crystallography of 1, circular dichroism of 2 and 3, and spectral studies of prepared derivatives. Compound 1 exhibited weak cytotoxicity toward the 1138 mutant yeast strain and the A2780 human ovarian cancer cell line.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Diterpenos/isolamento & purificação , Fabaceae/química , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Diterpenos/química , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Espectrometria de Massas , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Neoplasias Ovarianas , Folhas de Planta/química , Brotos de Planta/química , Caules de Planta/química , Estereoisomerismo , Suriname , Células Tumorais Cultivadas/efeitos dos fármacos , Leveduras/efeitos dos fármacosRESUMO
In addition to the known diterpene casearin G (1), two new clerodane diterpene casearins type, casearin S (2) and casearin T (3), were isolated from an acetylated bioactive CH(2)Cl(2)/MeOH extract from leaves of Casearia sylvestris. The diterpenes 1-3 exhibited moderate but selective activity towards the DNA-repair deficient yeast Saccharomyces cerevisiae mutants RAD 52YK and RS 321. The structures of 1-3 were established on the basis of NMR spectroscopic experiments