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

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 again...

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Bibliographic Details
Published in:ChemMedChem 2017-01, Vol.12 (2), p.177-182
Main Authors: Perreault, Martin, Maltais, René, Roy, Jenny, Dutour, Raphaël, Poirier, Donald
Format: Article
Language:English
Subjects:
aminosteroids
Animals
anticancer agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - therapeutic use
Antineoplastic Agents - toxicity
breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Design
Female
Humans
MCF-7 Cells
Mestranol - chemistry
Mestranol - therapeutic use
Mestranol - toxicity
metabolic stability
Mice
Mice, Nude
selective cytotoxicity
Transplantation, Heterologous
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Summary: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. The “pill” to fight cancer: A steroidal derivative of the contraceptive pill component mestranol, which was designed by adding a 2‐N‐piperazino side chain, was found to provide highly potent and selective anticancer activity against MCF‐7 breast cancer cells in vitro and in vivo.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201600482