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

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.

SUBMITTER: Motyan G

PROVIDER: S-EPMC6539495 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Mótyán Gergő G Gopisetty Mohana Krishna MK Kiss-Faludy Réka Eleonóra RE Kulmány Ágnes Á Zupkó István I Frank Éva É Kiricsi Mónika M

International journal of molecular sciences 20190502 9

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 th ...[more]

PMID: 31052484

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Project description:Prostate cancer (PCa) is a heterogeneous disease and ranked as the second leading cause of cancer-related deaths in males worldwide. The global burden of PCa keeps rising regardless of the emerging cutting-edge technologies for treatment and drug designation. There are a number of treatment options which are effectively treating localised and androgen-dependent PCa (ADPC) through hormonal and surgery treatments. However, over time, these cancerous cells progress to androgen-independent PCa (AIPC) which continuously grow despite hormone depletion. At this particular stage, androgen depletion therapy (ADT) is no longer effective as these cancerous cells are rendered hormone-insensitive and capable of growing in the absence of androgen. AIPC is a lethal type of disease which leads to poor prognosis and is a major contributor to PCa death rates. A natural product-derived compound, curcumin has been identified as a pleiotropic compound which capable of influencing and modulating a diverse range of molecular targets and signalling pathways in order to exhibit its medicinal properties. Due to such multi-targeted behaviour, its benefits are paramount in combating a wide range of diseases including inflammation and cancer disease. Curcumin exhibits anti-cancer properties by suppressing cancer cells growth and survival, inflammation, invasion, cell proliferation as well as possesses the ability to induce apoptosis in malignant cells. In this review, we investigate the mechanism of curcumin by modulating multiple signalling pathways such as androgen receptor (AR) signalling, activating protein-1 (AP-1), phosphatidylinositol 3-kinases/the serine/threonine kinase (PI3K/Akt/mTOR), wingless (Wnt)/ß-catenin signalling, and molecular targets including nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2) and cyclin D1 which are implicated in the development and progression of both types of PCa, ADPC and AIPC. In addition, the role of microRNAs and clinical trials on the anti-cancer effects of curcumin in PCa patients were also reviewed.

Dataset Information

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

Publications

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

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