Novel 4-Azapregnene Derivatives as Potential Anticancer Agents: Synthesis, Antiproliferative Activity and Molecular Docking Studies.

A series of novel 21 E -arylidene-4-azapregn-5-ene steroids has been successfully designed, synthesized and structurally characterized, and their antiproliferative activity was evaluated in four different cell lines. Within this group, the 21 E -(pyridin-3-yl)methylidene derivative exhibited significant cytotoxic activity in hormone-dependent cells LNCaP (IC 50 = 10.20 µM) and T47-D cells (IC 50 = 1.33 µM). In PC-3 androgen-independent cells, the steroid 21 E - p -nitrophenylidene-4-azapregn-5-ene was the most potent of this series (IC 50 = 3.29 µM). Considering these results, the 21 E -(pyridin-3-yl)methylidene derivative was chosen for further biological studies on T47-D and LNCaP cells, and it was shown that this azasteroid seems to lead T47-D cells to apoptotic death. Finally, molecular docking studies were performed to explore the affinity of these 4-azapregnene derivatives to several steroid targets, namely 5α-reductase type 2, estrogen receptor α, androgen receptor and CYP17A1. In general, compounds presented higher affinity to 5α-reductase type 2 and estrogen receptor α.