RESUMO
We report a rapid and efficient synthesis of A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives from dehydroepiandrosterone. Compounds were validated spectroscopically and structurally characterized by X-ray crystallography. Virtual screening by molecular docking against clinical targets of steroidal anticancer drugs (ERα, AR, Aromatase and CYP17A1) suggests that 17(E)-picolinylidene, but not 17α-picolyl androstanes could specifically interact with CYP17A1 (17α-hydroxylase) with similar geometry and affinity as Abiraterone, a 17-pyridinyl androstane drug clinically used in the treatment of prostate cancer. In addition, several 17(E)-picolinylidene androstanes demonstrated selective antiproliferative activity against PC3 prostate cancer cells, which correlates with Abiraterone antiproliferative activity and predicted CYP17A1 binding affinities. Based on these preliminary results, 17(E)-picolinylidene androstane derivatives could be a promising starting point for the development of new compounds for the treatment of prostate cancer.
Assuntos
Androstanos/química , Androstanos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Masculino , Simulação de Acoplamento Molecular , Próstata/efeitos dos fármacos , Próstata/enzimologia , Próstata/patologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Ligação Proteica , Esteroide 17-alfa-Hidroxilase/química , Esteroide 17-alfa-Hidroxilase/metabolismoRESUMO
Starting from the D-homo lactones of androst-4-en-3-one 3 and 4, prepared from 1 and 2, the new 17a homolactones 5-12, 14 and 15, were synthesized. The 4-hydroxy compounds 9 and 10 were obtained through the reaction of 4alpha,5alpha- (5 and 7) and 4beta,5beta- (6 and 8) epoxides with formic acid. The epoxides 5 and 6 were prepared from compound 3, and epoxides 7 and 8 from compound 4 by oxidation with H(2)O(2) under basic conditions. Compound 1 served as a starting substance for obtaining lactones 11-13. Oxidation of compound 1 with m-chloroperbenzoic acid yielded 11 and 12, but compound 13 gave 14. Compound 15 was obtained from 13 by oxidation with H(2)O(2) under basic conditions. The structures of epoxides 6 and 14 were confirmed by X-ray structural analysis. Cytotoxic activity against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER-, MDA-MB-231, and prostate cancer PC3) was evaluated. Compounds 6 and 14 showed strong activity against PC3, the IC(50) being 10.6 and 2.2 microM, respectively, whereas compounds 3 and 8 showed strong activity against MDA-MB-231 (IC(50) is 9.3 and 3.6 microM, respectively). Aromatase inhibition assay showed that the tested compounds 9, 10, and 14 possess lower activity compared to formestane.
Assuntos
Lactonas/síntese química , Lactonas/farmacologia , Esteroides/síntese química , Esteroides/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Oxirredução , Esteroides/químicaRESUMO
Starting from dehydroepiandrosterone (1) 17-picolyl (2), 17-picolinylidene (7), 17-picolinylidene-16-one (10 and 11), and 17-picolyl-16-one (15) derivatives of androst-5-ene were synthesized in one, two, four and five steps respectively. By the Oppenauer oxidation or dehydration of 2, 7, 10, and 11 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the corresponding A and B ring modified derivatives 3, 5, 6, 8, 9, and 12-14 were obtained. The structure of 2 was unambiguously proved by the appropriate X-ray structural analysis. Compounds 3, 5, 9, 12-14 showed inhibitory activity against the enzyme aromatase. Antibacterial activity, toxicity to brine shrimp Artemia salina, antitumor activity against three tumor cell lines (human cervix carcinoma HeLa cells, human melanoma FemX cells, and human myelogenous leukemia K562 cells) and toxicity against peripheral blood mononuclear cells were evaluated. Three tested compounds, namely 11, 13, and 15, showed strong activity against all three cell lines, the IC(50) values being in the range of 4-10 microM.
Assuntos
Androstenos/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Androstenos/síntese química , Androstenos/química , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Aromatase/metabolismo , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Linhagem Celular Tumoral , Feminino , Humanos , Concentração Inibidora 50 , Melanoma/tratamento farmacológico , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Starting from D-seco derivatives of 5-androstene 1-3, the D-homo lactones, 4 and 5, were synthesized. By the Oppenauer oxidation and/or by dehydration of 4 and 5 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil), the corresponding D-lactones 6-12 were obtained. The structures of 6 and 10 were unambiguously proved by the appropriate X-ray structural analysis. Anti-aromatase assay showed that tested compounds possess inhibition potency, however, two to four times smaller (IC50 from 0.2 to 0.7 microM, respectively) in comparison to aminoglutethimide (AG).