title: 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.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec City, Québec, G1V 4G2, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Perreault
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec City, Québec, G1V 4G2, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec City, Québec, G1V 4G2, Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec City, Québec, G1V 4G2, Canada.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Dutour
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec-Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec City, Québec, G1V 4G2, Canada.|Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, Québec, Canada.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008656:Mestranol / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D008819:Mice, Nude; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D008656:Mestranol
keywords: aminosteroids; anticancer agents; breast cancer; metabolic stability; selective cytotoxicity