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1.
Acta Pharm Sin B ; 13(12): 4934-4944, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38045040

RESUMO

Nuclear transporter importin-ß1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-ß1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-ß1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-ß1.

2.
Molecules ; 28(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36677570

RESUMO

Glochidpurnoids A and B (1 and 2), two new coumaroyl or feruloyl oleananes, along with 17 known triterpenoids (3-19) were obtained from the stems and twigs of Glochidion puberum. Their structures were elucidated by extensive spectroscopic data analyses, chemical methods, and single crystal X-ray diffraction. All compounds were screened for cytotoxicity against the colorectal cancer cell line HCT-116, and 2, 3, 5, 6, 11, and 17 showed remarkable inhibitory activities (IC50: 0.80-2.99 µM), being more active than the positive control 5-fluorouracil (5-FU). The mechanistic study of 2, the most potent compound, showed that it could induce endoplasmic reticulum (ER) stress-mediated apoptosis and improve the sensitivity of HCT-116 cells to 5-FU.


Assuntos
Neoplasias Colorretais , Malpighiales , Humanos , Apoptose , Fluoruracila/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Estresse do Retículo Endoplasmático
3.
J Am Chem Soc ; 144(38): 17522-17532, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36103720

RESUMO

Importins are overexpressed in many cancers and mediate the abnormal nuclear transport of oncogenic factors. The druggable potential of importins still remains unclear, largely because of the lack of potent inhibitors. Herein, the anti-castration-resistant prostate cancer (CRPC) screening of a Euphorbiaceae diterpenoid library followed by target fishing led to the identification of a highly potent importin-ß1 inhibitor, daphnane diterpenoid DD1. DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar concentrations and completely blocked tumor growth in preclinical models at an extremely low dosage. Mechanistic studies revealed that targeting of importin-ß1 by DD1 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of DD1 on importin-ß1 abolished this anti-CRPC effect. These findings suggest that importin-ß1 is an effective therapeutic target in CRPC and that DD1 as the most potent importin-ß1 inhibitor to date can be developed as therapeutics for treatment of this disease.


Assuntos
Diterpenos , Neoplasias de Próstata Resistentes à Castração , Linhagem Celular Tumoral , Proliferação de Células , Diterpenos/farmacologia , Humanos , Carioferinas/farmacologia , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
4.
Bioorg Chem ; 128: 106103, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35998520

RESUMO

Tigliane and rhamnofolane diterpenoids bearing glycosyl substituents are rarely found in nature. In the current study, seven new tigliane glycosides, euphorwallsides A - G (1-7), and five new rhamnofolane glycosides, euphorwallsides H - L (8-12), were isolated from the whole plants of Euphorbia wallichii. Their structures were elucidated by a combination of spectroscopic, computational, and chemical means. The aglycones of 1-5 represent a rare class of 13-deoxygenated tiglianes, while those of 8-12 represent the first examples of 4-deoxygenated rhamnofolanes. 2, 3, 5, 7, 8, and 12 showed significant neuroprotective effects on sodium nitroprusside (SNP)-induced neuronal death in pheochromocytoma cell line PC-12 at 10 µM, being more active than the clinical drug, edaravone. Mechanistic study revealed that the most active compound, 3, could inhibit reactive oxygen species (ROS) accumulation and restore the mitochondrial membrane potential via modulating the Nrf2 signaling pathway in PC-12 cells.


Assuntos
Euphorbia , Forbóis , Animais , Euphorbia/química , Glicosídeos/farmacologia , Estrutura Molecular , Estresse Oxidativo , Células PC12 , Ratos
5.
Cancer Lett ; 526: 352-362, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34798195

RESUMO

The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms were related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer.


Assuntos
Autofagia/efeitos dos fármacos , Diterpenos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Inibidores de MTOR/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Inibidores de MTOR/farmacologia , Masculino , Camundongos , Transdução de Sinais , Transfecção
6.
J Med Chem ; 64(14): 9926-9942, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34236840

RESUMO

Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent-kaurane diterpenoid library (1-25). With subsequent biological screening, 20 highly potent compounds (IC50s < 3 µM) were identified. Among them, 8,9-seco-ent-kaurane 6 displayed comparable activity (IC50s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,ß-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo, 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Croton/química , Diterpenos do Tipo Caurano/farmacologia , Descoberta de Drogas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
7.
J Org Chem ; 86(11): 7588-7593, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34014670

RESUMO

Compounds 1-3, the rare examples of 9,11-seco euphane or lanostane triterpenoids featuring an enol-hemiacetal functionality, were isolated from Euphorbia stracheyi. Their structures were elucidated by a combination of spectroscopic, computational, chemical, and single-crystal X-ray diffraction means, which enables the structure of previously published euphorol J to be revised as 1. 1-3 showed significant cytotoxicities on the breast cancer cell line MDA-MB-468 with IC50 values in the range of 2.9-3.9 µM.


Assuntos
Euphorbia , Triterpenos , Cristalografia por Raios X , Estrutura Molecular , Esteroides , Triterpenos/farmacologia
8.
Cancer Lett ; 509: 13-25, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33836250

RESUMO

Bladder cancer is a clinically heterogeneous disease with a poor prognosis. In the current study, anti-proliferation assay of a Euphorbiaceae diterpenoid library led to the identification of an anti-bladder cancer agent Jolkinolide B (JB). JB showed significant cytotoxicity against a panel of bladder cancer cell lines and suppressed the growth of cisplatin (CDDP)-resistant bladder cancer xenografts in single or combination treatments. Mechanistic study revealed that, besides inducing mitogen-activated protein kinase (MAPK)-related apoptosis, JB could trigger the paraptosis via activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and extracellular signal-regulated kinase (ERK) pathway. The excessive production of ROS could be induced by JB via inhibition of thioredoxin reductase 1 (TrxR1) and depletion of glutathione (GSH). Collectively, JB that targets thioredoxin and GSH systems to induce two distinct cell death modes may serve as a promising candidate in future anti-bladder cancer drug development.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxinas/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Tiorredoxina Redutase 1/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Eur J Med Chem ; 212: 113019, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33429247

RESUMO

Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFRL858R/T790M inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC50 value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC50 value of 0.008 µM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFRL858R/T790M-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
Nat Prod Res ; 35(9): 1497-1503, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-31437009

RESUMO

A preliminary research on the marine fungus Fusarium sp. XBB-9 resulted in a pair of novel bisindole alkaloid enantiomers, (+)- and (-)-fusaspoid A (1a/1b) and 12 diverse compounds. One strain many compound (OSMAC) method was used to enhance as many biosynthetic pathways as possible. The structures of the compounds were elucidated by spectroscopic analysis, and the absolute configuration of 1a was determined by X-ray single-crystal diffraction analysis. Compounds 1a and 1b were tested for cytotoxic activity against HCT-15, RKO cell lines, but were inactive. Compounds 1a and 1b were the first example of bisindole alkaloids isolated from fungus Fusarium sp. XBB-9.


Assuntos
Organismos Aquáticos/química , Fusarium/química , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Antineoplásicos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Alcaloides Indólicos/farmacologia , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo
11.
J Nat Prod ; 83(9): 2679-2685, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32902982

RESUMO

Twelve new polyketides, including a naphthoquinone derivative, penithoketone (1), and 11 chromone derivatives, penithochromones A-L (2-12), together with three known compounds (13-15) were isolated from the deep-sea-derived fungus Penicillium thomii YPGA3. The structures of the metabolites were elucidated based on extensive analyses of the spectroscopic data, and the configuration of 1 was resolved by quantum chemical calculations of NMR shifts and ECD spectra and comparisons to experimental data. Compound 1, containing a naphthoquinone-derived moiety substituted with a butenolide unit, represents a new modified naphthoquinone skeleton. Interestingly, the 5,7-dioxygenated chromone derivatives 2-13 possessed different alkyl acid or alkyl ester side chain lengths, and those with side chain lengths of seven carbon atoms were discovered from nature for the first time. The metabolites were evaluated for their cytotoxicity against four cancer cell lines; compounds 1 and 15 were found to be active, with IC50 values ranging from 4.9 to 9.1 µM.


Assuntos
Penicillium/química , Policetídeos/química , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oceanos e Mares , Microbiologia da Água
12.
Phytochemistry ; 176: 112395, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32353554

RESUMO

Eight previously undescribed diterpenoids, euphoroyleans A-H, including two cembranes, three ingenanes, two ent-atisanes, and one ent-kaurane, along with 22 known analogues were isolated from the whole plants of Euphorbia royleana. The structures of euphoroyleans A-H, including the absolute configurations, were elucidated by extensive spectroscopic analyses, chemical transformation, and single crystal X-ray diffractions. All the isolates were screened for their chemoreversal abilities on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) cancer cell line HepG2/DOX, and eight compounds exhibited significant activities. Among them, ingol-3,7,12-triacetate-8-benzoate, the most active MDR modulator with no obvious cytotoxicity, could enhance the efficacy of anticancer drug DOX to ca. 105 folds at 10 µM, being stronger than the positive drug verapamil. Mechanistic study revealed that ingol-3,7,12-triacetate-8-benzoate could inhibit the transport activity of P-gp rather than its expression, and the possible recognition mechanism between compounds and P-gp was predicted by molecular docking.


Assuntos
Diterpenos , Euphorbia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Simulação de Acoplamento Molecular , Estrutura Molecular
13.
J Asian Nat Prod Res ; 22(10): 927-934, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32293196

RESUMO

Two highly oxygenated nor-clerodane diterpenoids, crocleropenes A and B (1 and 2), together with four known compounds (3-6) were isolated from the leaves and twigs of Croton caudatus. Their structures were elucidated by combination of extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. 1 and 2 represent the first examples of nor-clerodane-3,5(10)-diene diterpenoids. Compounds 1 and 2 exhibited weak cytotoxicity in vitro against MCF-7 cancer cells with IC50 values of 35.8 and 40.2 µM, respectively. [Formula: see text].


Assuntos
Croton , Diterpenos Clerodânicos , Diterpenos , Núcleo Caudado , Humanos , Estrutura Molecular , Folhas de Planta
14.
Bioorg Chem ; 98: 103763, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32200324

RESUMO

Thirteen new jatrophane diterpenoids, euphoresulanes A-M (1-13), and seven known analogues (14-20) were isolated from the whole plants of Euphorbia esula. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of 1, 6, and 10 were confirmed by single crystal X-ray diffraction. Compounds 1-20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent cancer cell line HepG2/ADR, and 1, 2, 4, 6, and 8 exhibited comparable activity to the positive drugs. Euphoresulane H (8), the most active MDR modulator, could enhance the efficacy of anticancer drug adriamycin to ca. 33 folds at 5 µM. The structure-activity relationship (SAR) study revealed that the acyloxy substitution at C-9 is essential to the activity and presence of H-2 was favorable.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Euphorbia/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
15.
Mar Drugs ; 18(3)2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32188160

RESUMO

A chemical study of the ethyl acetate (EtOAc) extract from the deep-sea-derived fungus Penicillium thomii YPGA3 led to the isolation of a new austalide meroterpenoid (1) and seven known analogues (28), two new labdane-type diterpenoids (9 and 10) and a known derivative (11). The structures of new compounds 1, 9, and 10 were determined by comprehensive analyses via nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data. The absolute configurations of 1, 9, and 10 were determined by comparisons of experimental electronic circular dichroism (ECD) with the calculated ECD spectra. Compound 1 represented the third example of austalides bearing a hydroxyl group at C-5 instead of the conserved methoxy in other known analogues. To our knowledge, diterpenoids belonging to the labdane-type were discovered from species of Penicillium for the first time. Compound 1 showed cytotoxicity toward MDA-MB-468 cells with an IC50 value of 38.9 M. Compounds 2 and 11 exhibited inhibition against α-glucosidase with IC50 values of 910 and 525 M, respectively, being more active than the positive control acarbose (1.33 mM).


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Penicillium , Terpenos/farmacologia , Animais , Antineoplásicos/química , Antioxidantes/química , Linhagem Celular Tumoral/efeitos dos fármacos , Dicroísmo Circular , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Oceanos e Mares , Terpenos/química , alfa-Glucosidases/química
16.
Bioorg Chem ; 95: 103546, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911302

RESUMO

Twenty new ingol diterpenoids, euphornans A-T (1-20), representing a rare class of C-19-oxidated and H-2, H-3 ß-oriented ingols, were isolated from the seeds of Euphorbia marginata. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, ECD analysis, and single crystal X-ray diffraction. Compounds 1-20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent MDR cancer cell line HepG2/ADR, and 11, 14, and 18 were identified as potent MDR modulators that could enhance the efficacy of anticancer drug adriamycin to ca. 20 folds at 5 µM. The Pgp inhibition mechanism and brief structure-activity relationships (SARs) of these compounds were also discussed.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Diterpenos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Euphorbia/química , Cristalografia por Raios X , Diterpenos/química , Células Hep G2 , Humanos , Análise Espectral/métodos
17.
Org Lett ; 22(1): 106-109, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31829610

RESUMO

Jatrofolianes A (1) and B (2), which are two highly modified lathyrane diterpenoids, were isolated from Jatropha gossypiifolia. 1 incorporates an unusual transannular 1,3-dioxolane moiety, forming a unique 5/6/5/8/3 ring system, while 2 possesses a new 10,11:13,14-diseco-lathyrane skeleton with a 12-membered macrocyclic lactone ring. Their structures were determined by spectroscopic analysis, quantum chemical calculations, and single-crystal X-ray diffraction. 2 showed significant multidrug resistance (MDR) reversal activity to cancer cells HepG2/ADR and HCT-15/5-FU at 10 µM.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Jatropha/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
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