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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
Author(s) -
Perreault Martin,
Maltais René,
Roy Jenny,
Dutour Raphaël,
Poirier Donald
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600482
Subject(s) - mcf 7 , in vivo , in vitro , mestranol , breast cancer , chemistry , cancer research , pharmacology , medicine , cancer , stereochemistry , biology , biochemistry , human breast , population , genetics , research methodology , environmental health , family planning
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 .