Chemical synthesis, NMR analysis and evaluation on a cancer xenograft model (HL-60) of the aminosteroid derivative RM-133

• RM-133 is a new steroid derivative with promising anticancer activity on cell lines.
• A convergent six-step synthesis of androsterone derivative RM-133 was developed.
• RM-133 was synthesized on a multi-gram scale in only 2 weeks.
• NMR analysis revealed that RM-133 exists as a mixture of two conformers.
• RM-133 blocks the tumor growth in a leukemia model (HL-60 xenograft).

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%.

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