MCF-7型
体内
体外
美司曲诺
乳腺癌
化学
癌症研究
药理学
内科学
癌症
医学
立体化学
生物
生物化学
人体乳房
人口
遗传学
研究方法
环境卫生
计划生育
作者
Martin Perreault,René Maltais,Jenny Roy,Raphaël Dutour,Donald Poirier
出处
期刊:ChemMedChem
[Wiley]
日期:2017-01-06
卷期号:12 (2): 177-182
被引量:21
标识
DOI:10.1002/cmdc.201600482
摘要
Abstract 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}[(2 S )‐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 μ m .
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