Synthesis of Libraries of 16β‐Aminopropyl Estradiol Derivatives for Targeting Two Key Steroidogenic Enzymes

Abstract

Two libraries, each consisting of 48 16beta-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 16beta-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 1 17beta-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.

A New Nonestrogenic Steroidal Inhibitor of 17β-Hydroxysteroid Dehydrogenase Type I Blocks the Estrogen-Dependent Breast Cancer Tumor Growth Induced by Estrone

“…In fact, we could see that at a 50 mg/mouse/day dose uterine growth is stimulated from 22 mg for the OVX-CTR group to 29 mg for OVX-CC-156 group (P < 0.05). In counterpart, weights of the uterus from all PBRM dose groups (10, 50, and 250 mg/mouse/day), were not significantly different to those of the OVX-CTR group after 7 days of treatment (25,24, and 23 mg, respectively). Thus, these results confirmed that PBRM is nonestrogenic in vivo.…”

“…Our group has previously reported the synthesis of a number of E2 derivatives modified at position 16 (19,(24)(25)(26)(27)(28) for use as 17b-HSD1 inhibitors. In one of these studies, CC-156 (16b-(m-carbamoylbenzyl)-E2; Fig.…”

A Sequential Dual Cleavage of the Arylsulfamate Linker to Provide Both Sulfamate and Phenol Derivatives

“…However, products with higher purity could be obtained by performing a silica gel fi ltration or a fl ash chromatography [31]. Libraries of steroidal sulfamates have also been successfully generated in high yields and purities [31][32][33]. Table 2 Representation of all library members (arylsulfamate derivatives 31-55).…”

Contribution to the development of inhibitors of 17β-hydroxysteroid dehydrogenase types 1 and 7: Key tools for studying and treating estrogen-dependent diseases

“…The new linker can be used for the solid-phase synthesis of steroidal and non-steroidal compounds, thus adding to its potential [65][66][67]. Ciobanu and Poirier [68] thus synthesized two libraries of 16␤-aminopropyl-E2 derivatives 48 (48 sulfamates and 48 phenols) designed with the aim of targeting mainly the enzyme steroid sulfatase and, in addition, the enzyme 17␤-HSD1. Selected members of the phenol library developed by this methodology were tested for the inhibition of 17␤-HSD1.…”