RESUMO
New pregnene analogs of N-hydroxamic acid 6, imino-propane hydrazides 7 and 8 as well as the aryl amides 9-11, oxadiazole, pyrazole and sulfinyl analogs 13-15, via the hydrazide analog 5 of methyl ((5-pregnen-3ß,17ß-diol-15α-yl)thio)propanoate (4) were synthesized. The in vitro cytotoxic activities of selected synthesized steroids against two human prostate cancer cell lines (PC-3, and LNCaP-AI) were evaluated by MTT assay. Compound 10 was the most active cytotoxic agent among these steroids against PC-3 and LNCaP-AI cell lines with inhibition of 96.2%, and 93.6% at concentration levels of 10.0 µM and 91.8%, and of 79.8% at concentration of 1.0 µM, respectively. Molecular docking study of 10 showed a hydrogen bonding with the amino acid Asn705 residue of the receptor 1E3G, together with hydrophobic interactions. Therefore, compound 10 can be considered as a promising anticancer agent due to its potent cytotoxic activity.
Assuntos
Antineoplásicos , Pregnenos , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Simulação de Acoplamento Molecular , Pregnenos/síntese química , Pregnenos/química , Pregnenos/farmacologia , Receptores Androgênicos/químicaRESUMO
A new class of steroids is being synthesized for its ability to prevent intratumoral androgen production by inhibiting the activity of CYP17 hydroxylase enzyme. The scheme involved the synthesis of chalcone derivative of pregnenolone 5 which was further modified to the corresponding biaryl-chalcone pregnenolone analogs 16-25 using Suzuki-Miyaura cross-coupling reaction. The synthesized compounds were tested for activity using human CYP17α hydroxylase expressed in Escherichia coli. Compounds 21 was the most active inhibitor in this series, with IC50 values of 0.61µM and selectivity profile of 88.7% inhibition of hydroxylase enzyme. Molecular docking study of 21 was performed and showed the hydrogen bonds and hydrophobic interaction with the amino acid residues of the active site of CYP17.
Assuntos
Chalcona/análogos & derivados , Simulação de Acoplamento Molecular , Pregnenolona/química , Pregnenolona/farmacologia , Relação Quantitativa Estrutura-Atividade , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/metabolismo , Animais , Técnicas de Química Sintética , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Humanos , Pregnenolona/síntese química , Pregnenolona/metabolismo , Conformação Proteica , Ratos , Esteroide 17-alfa-Hidroxilase/químicaRESUMO
A new series of 17-(N-(arylimino)-5-pregnen-3ß-ol derivatives 19-32 as well as carboxylate and acrylate analogues of pregnenolone 37-40 were synthesized and evaluated for their inhibitory activity against human CYP17 hydroxylase expressed in Escherichia coli. Compounds 32 and 37 were the most potent analogues in this series, showing inhibition activity with IC50 = 2.11 and 1.29 µM, respectively. However, the analogue 37 revealed a better selectivity profile (83.21% inhibition of hydroxylase), which is a leading candidate for further development. Molecular docking study of 37 showed binding with the amino acid residues of CYP17 through hydrogen bonds and hydrophobic interaction.
