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

作者：Perreault Martin; Maltais Rene; Roy Jenny; Dutour Raphael; Poirier Donald^*

来源：ChemMedChem, 2017, 12(2): 177-182.

DOI：10.1002/cmdc.201600482

• aminosteroids
• anticancer agents
• breast cancer
• metabolic stability
• selective cytotoxicity

Anticancer structure-activity relationship studies on aminosteroid (5-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5-androstane-3,17-diol), which possesses high invitro and invivo 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-[17-ethynyl-17-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 50m.

• 出版日期2017-1-20