RESUMO
Due to its function as a regulator of drug-metabolizing enzymes and transporters, pregnane X receptor (PXR) represents an important factor involved in drug metabolism. In this work, we describe the discovery of diethylstilbestrol-based PXR modulators, which were designed from marine sulfated steroids with PXR agonistic activity, solomonsterols A and B, and our recently reported bazedoxifene scaffold-derived PXR antagonists. The methylated diethylstilbestrol derivative 1 displayed potent PXR agonistic activity with an EC50 value of 10.5 µM, whereas compounds 3, 4 and 6 (IC50 for 6 = 27.4 µM) and diethylstilbestrol (2) itself (IC50 = 14.6 µM) exhibited PXR antagonistic effects in HepG2 cells. The PXR modulatory effects of the synthesized diethylstilbestrol derivatives were further confirmed by the induction of PXR-regulated CYP3A4 expression with compound 1, as well as by the inhibition of the rifaximin-promoted up-regulation of CYP3A4 expression with 2 and its derivative 6.
Assuntos
Dietilestilbestrol/farmacologia , Receptores de Esteroides/agonistas , Receptores de Esteroides/antagonistas & inibidores , Citocromo P-450 CYP3A/biossíntese , Citocromo P-450 CYP3A/metabolismo , Dietilestilbestrol/síntese química , Dietilestilbestrol/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Células Hep G2 , Humanos , Modelos Moleculares , Estrutura Molecular , Receptor de Pregnano X , Rifamicinas/antagonistas & inibidores , Rifamicinas/farmacologia , Rifaximina , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacosRESUMO
Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug-metabolizing enzymes and transporters. The overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multidrug resistance in anticancer treatments. We describe the discovery of novel bazedoxifene-scaffold-based PXR antagonists inspired by the marine sulfated steroids solomonsterol A and B as natural leads. A luciferase reporter assay on a PXR-transfected HepG2 cell line identified compounds 19-24 as promising PXR antagonists. Further structure-activity relationship studies of the most active PXR antagonist from the series (compound 20, IC50 = 11 µM) revealed the importance of hydroxyl groups as hydrogen-bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC50 = 14 µM), in addition to the downregulation of PXR expression, exhibited inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase-I drug metabolism.
