New CYP17 Hydroxylase Inhibitors: Synthesis, Biological Evaluation, QSAR, and Molecular Docking Study of New Pregnenolone Analogs

Abstract

A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5-aryl-1,3,4-thiadiazol-2-yl)-imino-pregnenolone derivatives 11-15 were more active than the sulfonate 24-31 and the ester 37-41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.5 µM compared with the standard abiraterone (IC50 = 0.07 µM). However, the analogs 11 and 25 showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.

Synthesis, characterization, physical and biological properties of some cholesterol derivatives

“…The reaction was monitored by TLC (n-hexane:ethyl acetate, 2:3, v:v) [21]. The purity of products were checked by SiO2 column chromatography (5 g) by mixture (MeOH:CHCl3, 3:2, v:v) as elution afforded the pure desired products (Scheme 1).…”

Exploration of new 3α-pregnenolone ester analogues via Mitsunobu reaction, their anti-HIV activity and molecular modeling study

“…Recently, we prepared in our laboratory the iminebenzothiadiazole analogues of pregnenolone molecule [37], aiming to evaluate their cytochrome CYP17 hydroxylase and HIV inhibition activity. In our present work, we have selected β-pregnenolone a starting material for the synthesis of a new series of α-ester of pregnenolone analogues, with inversion in configuration at C-3, by applying of Mitsunobu reaction.…”

“…This pregnenolone derivative was designed as an inhibitor of the enzyme 17α-hydroxylase/C17,20-lyase (CYP17A1) [30,36] which catalyzes two key reactions in steroid hormone biosynthesis. Much more recently, we have synthesized new series of pregnenolone having imino-benzothiazoles 4 at C-20, which showed remarkable inhibition of CYP17 hydroxylase activity, Figure 1 [37].…”

A new pregnenolone analogues as privileged scaffolds in inhibition of CYP17 hydroxylase enzyme. Synthesis and in silico molecular docking study

“…We are interested in the synthesis and characterization of new steroidal compounds with selective inhibition of CYP17 hydroxylase enzyme properties, for use in the development of more effective treatments of breast and prostate cancer. Building on our previous work [30], in the present study we reported the synthesis of new 17-pregnenoloneimine derivatives with their CYP17 hydroxylase enzyme inhibition activity and the molecular modeling study. …”