RESUMO
A novel series of 3-(4-fluorophenyl)-1H-pyrazole derivatives were synthesized and evaluated for their antiproliferative activity against two prostate cancer cell lines (LNCaP and PC-3) and androgen receptor target gene prostate-specific antigen (PSA) inhibitory activity in LNCaP cells. Several compounds showed potent antiproliferative activity against LNCaP cells and showed a promising PSA downregulation rate. Among these, compound 10e selectively inhibited LNCaP cell growth with an IC50 value of 18 µmol/l and showed a PSA downregulation rate of 46%, which was better than the lead compound T3.
Assuntos
Compostos de Anilina/química , Antineoplásicos/química , Benzamidas/química , Pirazóis/química , Compostos de Anilina/síntese química , Compostos de Anilina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Masculino , Antígeno Prostático Específico/antagonistas & inibidores , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
Androgen receptor (AR) is an attractive target for the treatment of prostate cancer. An integrated pharmacophore-based and docking-based virtual screening approach was applied to identify novel AR antagonists with a distinct scaffold. The candidate compounds were evaluated for their abilities to inhibit prostate cancer cell proliferation and AR target gene prostate-specific antigen gene expression as well as the binding affinity to AR. A potent lead compound, T3, was discovered with the ability to inhibit prostate-specific antigen expression, with a similar binding affinity to AR, and with antiproliferative effects on AR-positive prostate cancer cells similar to that of MDV3100.