Synthesis of libraries of 16β-aminopropyl estradiol derivatives for targeting two key steroidogenic enzymes

Two libraries, each consisting of 48 16 beta-aminopropyl estradiol derivatives, phenols and sulfamates, respectively, were synthesized by solid-phase parallel chemistry through a seven-step reaction sequence. Following the attachment of a C18-steroid sulfamate precursor on a trityl chloride resin, diversity elements were first introduced on the 16 beta-aminopropyl chain of the steroid by acylation reactions with eight Fmoc-amino acids. After deprotection, the free amine function of the resulting compounds was reacted with six carboxylic acids for the introduction of a second diversity level. The two variants employed for the cleavage of compounds from the solid support, acidic and nucleophilic, allowed the corresponding libraries of sulfamate and phenol derivatives in yields of 8-50% and 13-58% to be obtained with an average HPLC purity of 94% and 91%, respectively. Potent steroid sulfatase inhibitors and interesting SAR results were generated from the screening of the sulfamate library. Furthermore, moderate inhibitors of type 117 beta-HSD resulted from the partial screening of phenol library. Thus, these two categories of compounds were synthesized to rapidly identify potential inhibitors of steroid biosynthesis for the hormonal therapy of estrogen-dependent diseases, and also to demonstrate the versatility and efficiency of the recently developed sulfamate linker.