Chemical synthesis, NMR analysis and evaluation on a cancer xenograft model (HL-60) of the aminosteroid derivative RM-133.
The aminosteroid derivative RM-133 has been reported to be a promising pro-apoptotic agent showing activity on various cancer cell lines. Following the development of solid-phase synthesis that generated a series of libraries of aminosteroid derivatives, we now report the development of a convenient liquid phase chemical synthesis of RM-133, the most promising candidate, in order to obtain sufficient quantities to proceed with the first preclinical assays. A simple and convergent six-step synthesis was designed and allowed the preparation of a gram-quantity scale of RM-133. This aminosteroid derivative was also fully characterized by NMR experiments which revealed an interesting mixture of conformers. Finally, the in vivo potency of RM-133 was evaluated on a xenograft model in nude mice with HL-60 tumors, which has resulted in the blocking of tumor progression by 57%.
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), and Faculty of Medicine (Université Laval), Québec, Québec G1V 4G2, Canada.
René
R
Maltais
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), and Faculty of Medicine (Université Laval), Québec, Québec G1V 4G2, Canada.
Audrey
A
Hospital
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), and Faculty of Medicine (Université Laval), Québec, Québec G1V 4G2, Canada.
Audrey
A
Delhomme
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), and Faculty of Medicine (Université Laval), Québec, Québec G1V 4G2, Canada.
Jenny
J
Roy
Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4), and Faculty of Medicine (Université Laval), Québec, Québec G1V 4G2, Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
Donald
D
Poirier
D000736:Androstenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000736:Androstenes; D000970:Antineoplastic Agents; C000594943:RM-133 aminosteroid
Cancer; Leukemia; NMR; Synthesis; Xenograft