Design of a Mestranol 2-N-Piperazino-Substituted Derivative Showing Potent and Selective in vitro and in vivo Activities in MCF-7 Breast Cancer Models

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• 作者：Dr. Martin Perreault ; Dr. René ; Maltais ; Dr. Jenny Roy ; Raphaë ; l Dutour and Prof. Donald Poirier
• 刊名：ChemMedChem
• 出版年：2017
• 出版时间：January 20, 2017
• 年：2017
• 卷：12
• 期：2
• 页码：177-182
• 全文大小：752K
• ISSN：1860-7187

文摘

Anticancer structure–activity relationship studies on aminosteroid (5α-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2β-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5α-androstane-3α,17β-diol), which possesses high in vitro and in vivo activities against several cancer cells, and selectivity over normal cells. However, the relatively weak metabolic stability of RM-133 has been a drawback to its progression toward clinical trials. We investigated the replacement of the androstane backbone by a more stable mestranol moiety. The resulting compound, called RM-581 ({4-[17α-ethynyl-17β-hydroxy-3-methoxyestra-1,3,5(10)-trien-2-yl]piperazin-1-yl}[(2S)-1-(quinolin-2-ylcarbonyl)pyrrolidin-2-yl]methanone), was synthesized efficiently in only five steps from commercially available estrone. In comparison with RM-133, RM-581 was found to be twice as metabolically stable, retains potent cytotoxic activity in breast cancer MCF-7 cell culture, and fully blocks tumor growth in a mouse xenograft model of breast cancer. Advantageously, the selectivity over normal cells has been increased with this estrane version of RM-133. In fact, RM-581 showed a better selectivity index (15.3 vs. 3.0) for breast cancer MCF-7 cells over normal breast MCF-10A cells, and was found to be nontoxic toward primary human kidney proximal tubule cells at doses reaching 50 μm.