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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-09, Vol.27 (18), p.6126
• Main Authors: Brito, Vanessa, Santos, Adriana Oliveira, Alves, Gilberto, Almeida, Paulo, Silvestre, Samuel
• Format: Article
• Language: English
• Subjects: 4-azapregnenes; 4-azasteroids; Affinity; aldol condensation; Androgen receptors; Androgens; antiproliferative activity; Antiproliferatives; Apoptosis; Bioavailability; Breast cancer; Cell death; Cell growth; Cell lines; Cytotoxicity; Delta cells; Drug resistance; Dutasteride; Estrogen receptors; Estrogens; Fibroblasts; Microscopy; Molecular docking; NMR; Nuclear magnetic resonance; Prostate cancer; Reductases; Steroid hormones; Steroids
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27186126

A series of novel 21E-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 21E-(pyridin-3-yl)methylidene derivative exhibited significant cytotoxic activity in hormone-dependent cells LNCaP (IC50 = 10.20 µM) and T47-D cells (IC50 = 1.33 µM). In PC-3 androgen-independent cells, the steroid 21E-p-nitrophenylidene-4-azapregn-5-ene was the most potent of this series (IC50 = 3.29 µM). Considering these results, the 21E-(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.