Oxazolinyl derivatives of androst-16-ene as inhibitors of CYP17A1 activity and prostate carcinoma cells proliferation: Effects of substituents in oxazolinyl moiety.

Steroid derivatives modified with nitrogen containing heterocycles are known to inhibit activity of steroidogenic enzymes, decrease proliferation of cancer cells and attract attention as promising anticancer agents. Specifically, 2'-(3ß-hydroxyandrosta-5,16-dien-17-yl)-4',5'-dihydro-1',3'-oxazole 1a potently inhibited proliferation of prostate carcinoma cells. In this study we synthesized and investigated five new derivatives of 3ß-hydroxyandrosta-5,16-diene comprising 4'-methyl or 4'-phenyl substituted oxazolinyl cycle 1 (b-f). Docking of compounds 1 (a-f) to CYP17A1 active site revealed that the presence of substitutents at C4' atom in oxazoline cycle, as well as C4' atom configuration, significantly affect docking poses of compounds in the complexes with enzyme. Testing of compounds 1 (a-f) as CYP17A1 inhibitors revealed that the only compound 1a, comprising unsubstituted oxazolinyl moiety, demonstrated strong inhibitory activity, while other compounds 1 (b-f) were slightly active or non active. Compounds 1 (a-f) efficiently decreased growth and proliferation of prostate carcinoma LNCaP and PC-3 cells at 96 h incubation; the effect of compound 1a was the most powerful. Compound 1a efficiently stimulated apoptosis and caused PC-3 cells death, that was demonstrated by a direct comparison of pro-apoptotic effects of compound 1a and abiraterone.

New steroidal oxazolines, benzoxazoles and benzimidazoles related to abiraterone and galeterone.

Seven new oxazoline, benzoxazole and benzimidazole derivatives were synthesized from 3ß-acetoxyandrosta-5,16-dien-17-carboxylic, 3ß-acetoxyandrost-5-en-17ß-carboxylic and 3ß-acetoxypregn-5-en-21-oic acids. Docking to active site of human 17α-hydroxylase/17,20-lyase revealed that all oxazolines, as well as benzoxazoles and benzimidazoles comprising Δ16 could form stable complexes with enzyme, in which steroid moiety is positioned similarly to that of abiraterone and galeterone, and nitrogen atom coordinates heme iron, while 16,17-saturated benzoxazoles and benzimidazoles could only bind in a position where heterocycle is located nearly parallel to heme plane. Modeling of the interaction of new benzoxazole and benzimidazole derivatives with androgen receptor revealed the destabilization of helix 12, constituting activation function 2 (AF2) site, by mentioned compounds, similar to one induced by known antagonist galeterone. The synthesized compounds inhibited growth of prostate carcinoma LNCaP and PC-3 cells at 96 h incubation; the potency of 2'-(3ß-hydroxyandrosta-5,16-dien-17-yl)-4',5'-dihydro-1',3'-oxazole and 2'-(3ß-hydroxyandrosta-5,16-dien-17-yl)-benzimidazole was superior and could inspire further investigations of these compounds as potential anti-cancer agents.