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

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.

Inhibition of estrone sulfate-induced uterine growth by potent nonestrogenic steroidal inhibitors of steroid sulfatase.

The present study describes the biological in vitro and in vivo evaluation of 2-methoxy derivatives of estrogenic inhibitors of steroid sulfatase, namely 3-sulfamoyloxy-17alpha-p-tert-butylbenzyl(or benzyl)-1,3,5 (10)-estratrien-17beta-ols. The addition of the 2-methoxy group conserves the potent inhibitory effect on steroid sulfatase activity (IC(50)s of 0.024 and 0.

Solid-phase parallel synthesis of 17alpha-substituted estradiol sulfamate and phenol libraries using the multidetachable sulfamate linker.

We report an application of the multidetachable sulfamate linker in the synthesis of two model libraries of N-derivatized 17alpha-piperazinomethyl estradiols (phenols and sulfamates) by solid-phase parallel chemistry. The solid-phase precursor, a 3-sulfamoyl-17alpha-(N-trifluoroacetyl-piperazinomethyl) estradiol, was synthesized in solution from estrone and loaded efficiently onto trityl chloride resin as polymeric support. After cleavage of the trifluoroacetyl protecting group, sequential acylation reactions with five Fmoc-protected amino acids and five carboxylic acids were performed to introduce two levels of molecular diversity.

3Beta-sulfamate derivatives of C19 and C21 steroids bearing a t-butylbenzyl or a benzyl group: synthesis and evaluation as non-estrogenic and non-androgenic steroid sulfatase inhibitors.

A series of C19 and C21 steroids bearing one or two inhibiting groups (3beta-sulfamate and 17alpha- or 20(S)-t-butylbenzyl or benzyl) were synthesized and tested for inhibition of steroid sulfatase activity. When only a sulfamate group was added to dehydroepiandrosterone, androst-5-ene-3beta,17beta-diol, pregnenolone and 20-hydroxy-pregnenolone, no significant inhibition of steroid sulfatase occurred at concentrations of 0.3 and 3 microM.

A multidetachable sulfamate linker successfully used in a solid-phase strategy to generate libraries of sulfamate and phenol derivatives.

The sulfamates and phenols constitute two families of compounds with numerous interesting biological properties. Using the ability of a new multidetachable sulfamate linker to generate these two families of compounds from the same resin, we designed and synthesized libraries of estradiol derivatives, sulfamoylated or not. A C-16beta side chain was then judiciously diversified to target two key steroidogenic enzymes, the steroid sulfates and the type 1 17beta-HSD.

Nonsteroidal compounds designed to mimic potent steroid sulfatase inhibitors.

Chemical synthesis and enzyme inhibition results are reported for a series of nonsteroidal sulfatase inhibitors, 1-(p-sulfamoyloxyphenyl)-5-(p-t-butylbenzyl)-5-alkanols and the lower active phenolic analogues. These compounds conserve some structural elements from the previously reported potent steroidal inhibitor 3-O-sulfamate-17alpha-(p-t-butylbenzyl)-17beta-hydroxy-estra-1,3,5(10)-triene, while the C18-methyl group and the hydrocarbon backbone represented by the steroid rings B, C, and D were replaced with a free conformational chain. Using estrone sulfate (100 microM) as substrate and homogenate of transfected HEK-293 cells as source of steroid sulfatase activity, the IC(50) values of the best inhibitors, the undecanol derivatives, were 0.