Anti-Cancer Activity of Novel Dihydrotestosterone-Derived Ring A-Condensed Pyrazoles on Androgen Non-Responsive Prostate Cancer Cell Lines

International Journal of Molecular Sciences

MohanaKrishna Gopisetty¹  Mónika Kiricsi¹  Gergő Mótyán²  RékaEleonóra Kiss-Faludy²  Éva Frank²  Ágnes Kulmány³  István Zupkó³ 

[1] Department of Biochemistry and Molecular Biology, University of Szeged, Közép fasor 52., H-6726 Szeged, Hungary;Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary;Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary;

关键词: dihydrotestosterone;    heterocyclization;    pyrazoles;    regioselectivity;    prostate cancer;    anti-cancer effect;    apoptosis;   

DOI  :  10.3390/ijms20092170

来源: DOAJ

【 摘 要 】

Regioselective synthesis of novel ring A-fused arylpyrazoles of dihydrotestosterone (DHT) was carried out in two steps under facile reaction conditions. Aldol condensation of DHT with acetaldehyde afforded a 2-ethylidene derivative regio- and stereo-selectively, which was reacted with different arylhydrazines in the presence of iodine via microwave-assisted oxidative cyclization reactions. The 17-keto analogs of steroidal pyrazoles were also synthesized by simple oxidation in order to enlarge the compound library available for pharmacological studies and to obtain structure−activity relationship. The antiproliferative activities of the structurally related heteroaromatic compounds were tested in vitro on human cervical and breast adenocarcinoma cell lines (HeLa, MCF-7 and MDA-MB-231) and on two androgen-independent malignant prostate carcinoma cell lines (PC-3 and DU 145). Based on primary cytotoxicity screens and IC₅₀ assessment, a structure-function relationship was identified, as derivatives carrying a hydroxyl group on C-17 exhibit stronger activity compared to the 17-one counterparts. Cancer cell selectivity of the derivatives was also determined using non-cancerous MRC-5 cells. Furthermore, the proapoptotic effects of some selected derivatives were verified on androgen therapy refractive p53-deficient PC-3 cells. The present study concludes that novel DHT-derived arylpyrazoles exert cancer cell specific antiproliferative activity and activate apoptosis in PC-3 cells.

【 授权许可】

Unknown