Identification of fused 16β,17β-oxazinone-estradiol derivatives as a new family of non-estrogenic 17β-hydroxysteroid dehydrogenase type 1 inhibitors.

A new family of cyclic carbamate-estradiol derivatives has been designed to remove the intrinsic estrogenic activity of a parent acyclic compound reported as a potent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). The synthesis of two series of fused 16β,17β-oxazinone-estradiol derivatives, saturated compounds 7a-d and unsaturated compounds 10a-d, led to the identification of 10b, a 17β-HSD1 inhibitor (IC50 = 1.4 μM) without estrogenic activity in estrogen-sensitive T-47D cells.

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.