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.

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}[(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.

• Authors: Martin Perreault, René Maltais, Jenny Roy, Raphaël Dutour, Donald Poirier
• Journal: ChemMedChem (ChemMedChem) Vol. 12 Issue 2 Pg. 177-182 (01 20 2017) ISSN: 1860-7187 [Electronic] Germany
• PMID: 28060448 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Mestranol

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use, toxicity)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Design
• Female
• Humans
• MCF-7 Cells
• Mestranol (chemistry, therapeutic use, toxicity)
• Mice
• Mice, Nude
• Transplantation, Heterologous