Anti-Cancer Activity of Novel Dihydrotestosterone-Derived Ring A-Condensed Pyrazoles on Androgen Non-Responsive Prostate Cancer Cell Lines.
Int J Mol Sci
; 20(9)2019 May 02.
Article
em En
| MEDLINE
| ID: mdl-31052484
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Pirazóis
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Di-Hidrotestosterona
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Antineoplásicos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article