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

Gergő Mótyán,Éva Frank,Réka Eleonóra Kiss-Faludy,Ágnes Kulmány,Mohana Krishna Gopisetty,Mónika Kiricsi,István Zupkó

doi:10.3390/ijms20092170

Gergő Mótyán, Éva Frank + Show 5 more

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https://doi.org/10.3390/ijms20092170

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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.

Highlights

Endogenous androgenic-anabolic steroids (AAS), such as testosterone (T) and its more active derivative, dihydrotestosterone (DHT) play a key role in the development and progression of hormone-dependent prostate cancer in men [1] and may exert a direct activating or inhibitory effect on the growth of certain female breast cancers primarily by influencing the androgen receptor (AR) signaling pathway [2,3].Since AR signaling is a substantial factor in malignant cell proliferation within the prostate tissue [4,5], the first-line therapy often involves hormone deprivation either via surgical manipulation of the endocrine system or by the exogenous administration of drugs
We previously demonstrated that different heteroaryl-fused derivatives of DHT exert significant antiproliferative effect in vitro on human cancer cell lines of diverse origins [21,22,23]
Prostate cancers that are insensitive to androgen blockade or those which are hormone-refractory after hormone and radiotherapy are the most challenging

Summary

Introduction

Since AR signaling is a substantial factor in malignant cell proliferation within the prostate tissue [4,5], the first-line therapy often involves hormone deprivation either via surgical manipulation of the endocrine system or by the exogenous administration of drugs. These procedures will reduce the levels of sex hormones by inhibiting their production, or block the action of the endogenous ligand by binding to the hormone receptor, thereby preventing its activation [6]. Early studies have demonstrated proliferation promoting as well as antiproliferative effects of androgens on cell activity, depending largely on the specific breast cancer subtype [9]

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