RESUMO
Etodolac hydrazide and a novel series of etodolac hydrazide-hydrazones 3-15 and etodolac 4-thiazolidinones 16-26 were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR, (13)C NMR, HREI-MS) methods. Some selected compounds were determined at one dose toward the full panel of 60 human cancer cell lines by the National Cancer Institute (NCI, Bethesda, USA). 2-(1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetic acid[(4-chlorophenyl)methylene]hydrazide 9 demonstrated the most marked effect on the prostate cancer cell line PC-3, with 58.24% growth inhibition at 10(-5) M (10 µM). Using the MTT colorimetric method, compound 9 was evaluated in vitro against the prostate cell line PC-3 and the rat fibroblast cell line L-929, for cell viability and growth inhibition at different doses. Compound 9 exhibited anticancer activity with an IC(50) value of 54 µM (22.842 µg/mL) against the PC-3 cells and did not display any cytotoxicity toward the L-929 rat fibroblasts, compared to etodolac. In addition, this compound was evaluated for caspase-3 and Bcl-2 activation in the apoptosis pathway, which plays a key role in the treatment of cancer.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Etodolac/análogos & derivados , Etodolac/farmacologia , Hidrazonas/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Etodolac/síntese química , Etodolac/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Concentração Inibidora 50 , Masculino , Neoplasias/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Análise EspectralRESUMO
A novel series of new etodolac hydrazide derivatives, 1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]-4-alkyl/aryl thiosemicarbazides [3a-h] have been synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, 1H-NMR, 13C-NMR and LC-MS) methods. Inhibition of hepatitis C virus NS5B RNA dependent RNA polymerase activity by etodolac thiosemicarbazides was evaluated in vitro by primer dependent elongation assays. The most active compounds of this series were 3a (SGK 224), 3d (SGK 227) and 3e (SGK 229) with IC50 values of 18.7 µM, 29.2 µM and 16.8 µM, respectively. Binding mode investigations of the most active compound 1-[2-(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)acetyl]-4-allyl thiosemicarbazide (3e) suggested that TP-II of HCV NS5B polymerase may be the potential binding site for etodolac thiosemicarbazides and provided clues for modifications to improve the potency of etodolac derivatives.