RESUMO
In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 microM against NL4-3, 0.021 microM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 microM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.
Assuntos
Fármacos Anti-HIV/síntese química , Ácido Oleanólico/análogos & derivados , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Farmacorresistência Viral , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/virologia , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Relação Estrutura-AtividadeRESUMO
As part of a study on potential antitumor agents from rainforest plants, two new pterocarpans, rautandiol A (1) and rautandiol B (2), together with eight known compounds, were isolated from Neorautanenia mitis. Among the compounds isolated, rotenone (3) and 12-hydroxyrotenone (4) showed significant cytotoxic activity with IC(50) values of 0.008-0.010 and 0.04-0.06 microg/mL against MCF-7 and A-549 cells, respectively.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Fabaceae/química , Plantas Medicinais/química , Pterocarpanos/isolamento & purificação , Pterocarpanos/farmacologia , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pterocarpanos/química , Tanzânia , Células Tumorais CultivadasRESUMO
Seven alkaloids (1-7) were isolated from the stem bark of Alangium longiflorum. Compound 1, (-)-10-O-demethylisocephaeline, was isolated for the first time as a naturally occurring product from a plant source. All structures were elucidated by detailed spectroscopic analysis. Biological evaluation showed that 2, 10-O-demethylcephaeline, exhibited potent cytotoxic activity against human lung carcinoma (A549) and breast adenocarcinoma (MCF-7) with ED(50) values of 0.013 and 0.062 microM, respectively. The stereoisomer 1 was less potent than 2, and related compounds with different hydroxy/methoxy substitution patterns were also less potent or inactive. Thus, compound 2 merits attention as a cytotoxic lead for further study.
Assuntos
Alangiaceae/química , Alcaloides/química , Alcaloides/farmacologia , Terpenos/síntese química , Terpenos/farmacologia , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estrutura Molecular , Casca de Planta/química , EstereoisomerismoRESUMO
In continuation of our previous report, cimigenol (1) and 15 related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)--induced Epstein-Barr virus early antigen (EBV-EA) activation assay. Cimigenol-3,15-dione (2) displayed the greatest potency (100% inhibition at 1000 mol ratio/TPA) and consequently was further examined for antitumor-promoting activity in a two-stage carcinogenesis assay of mouse skin tumors (DMBA/TPA). In this assay, compound 2 showed significant activity, reducing the number of papillomas per mouse to 48% of the control group at 20 weeks. In addition, compounds 1 and 2 were examined for antitumor-initiating activity in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite as an initiator and TPA as a promoter. Results showed that these two triterpenoids were almost equipotent with epigallocatechin gallate (EGCG) and slightly more potent than tocinol (group V), the positive controls. Thus, compounds 1 and 2 exhibited not only strong antitumor-promoting activity but also significant antitumor-initiating effect on mouse skin. These data suggest that both compounds might be valuable chemopreventors.
Assuntos
Anticarcinógenos/farmacologia , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Animais , Anticarcinógenos/química , Feminino , Lanosterol/química , Camundongos , Camundongos Endogâmicos ICR , Papiloma/prevenção & controle , Neoplasias Cutâneas/prevenção & controleRESUMO
Cimigenol (1) and 39 related compounds were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. Structure-activity relationship analysis indicated that compound 1 showed the highest activity and also exhibited significant inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that 1 and the related compounds might be valuable anti-tumor promoters.