Preparation of 6beta-estradiol derivative libraries as bisubstrate inhibitors of 7beta-hydroxysteroid dehydrogenase type using the multidetachable sulfamate linker.

Combinatorial chemistry is a powerful tool used to rapidly generate a large number of potentially biologically active compounds. In our goal to develop bisubstrate inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) that interact with both the substrate (estrone or estradiol) and the cofactor (NAD(P)H) binding sites, we used parallel solid-phase synthesis to prepare three libraries of 16beta-estradiol derivatives with two or three levels of molecular diversity. From estrone, we first synthesized a sulfamate precursor that we loaded on trityl chloride resin using the efficient multidetachable sulfamate linker strategy recently developed in our laboratory.

Improved synthesis of EM-1745, preparation of its C17-ketone analogue and comparison of their inhibitory potency on 17beta-hydroxysteroid dehydrogenase type 1.

Endocrine therapies are widely used for the treatment of estrogen-sensitive diseases. 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is involved in the last step of the biosynthesis of potent estrogen estradiol (E(2)). This enzyme catalyzes the reduction of the C17-ketosteroid estrone (E(1)) into the C17beta-hydroxy steroid E(2) using the cofactor NAD(P)H.

Benzoboroxoles as efficient glycopyranoside-binding agents in physiological conditions: structure and selectivity of complex formation.

In contrast to normal boronic acids, o-hydroxymethyl phenylboronic acid (benzoboroxole) has the capability of complexing glycopyranosides efficiently in neutral water. The measurement of association constants with a panel of model hexopyranosides indicates that the preferred mode of binding is through a cis-3,4-diol, such as that found in galactopyranosides, and mass spectrometric studies support a 1:1 binding stoichiometry. The complexation of glucopyranosides is weaker, and they are bound through their 4,6-diol unit.

Chemical synthesis and in vitro biological evaluation of a phosphorylated bisubstrate inhibitor of type 3 17beta-hydroxysteroid dehydrogenase.

Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) catalyzes the last step in the biosynthesis of the potent androgen testosterone (T) by selectively reducing the C17 ketone of 4-androstene-3,17-dione (delta4-dione), with NADPH as cofactor. This enzyme is thus an interesting therapeutic target for androgen-sensitive diseases. Using an efficient convergent chemical approach we synthesized a phosphorylated version of the best delta4-dione/adenosine hybrid inhibitor of type 3 17beta-HSD previously reported.

Design, synthesis and in vitro evaluation of 4-androstene-3,17-dione/adenosine hybrid compounds as bisubstrate inhibitors of type 3 17beta-hydroxysteroid dehydrogenase.

Steroidogenic enzyme type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is an important therapeutic target for androgen-sensitive diseases. This enzyme selectively reduces the C17 ketone of 4-androstene-3,17-dione (Delta4-dione), thus producing testosterone (T) using NADPH as cofactor. Our group previously synthesized hybrid (estradiol/adenosine) inhibitors that successfully inhibit the biosynthesis of the potent estrogen estradiol by type 1 17beta-HSD.

Estradiol-adenosine hybrid compounds designed to inhibit type 1 17beta-hydroxysteroid dehydrogenase.

The steroidogenic enzyme type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the synthesis of estradiol (E(2)), a hormone well-known to stimulate the growth of estrogen-sensitive tumors. To obtain compounds able to control E(2) formation, two moieties were linked with a methylene side chain: an adenosine moiety for interacting with the cofactor-binding site and an E(2) moiety for interacting with the substrate-binding site. When tested as inhibitors of type 1 17beta-HSD, the hybrid compounds inhibited the reductive activity (E(1) into E(2)) with IC(50) values ranging from 52 to 1,000 nM.

Synthesis of simplified hybrid inhibitors of type 1 17beta-hydroxysteroid dehydrogenase via cross-metathesis and sonogashira coupling Reactions.

[structure: see text] The inhibitor of type 1 17beta-hydroxysteroid dehydrogenase EM-1745 (1) exhibits affinity for both the substrate (estrone or estradiol) and the cofactor (NAD(P)H) binding domains. However, to increase its bioavailability, this compound needs to be simplified. The efficient and convergent synthesis of simplified substrate/cofactor hybrid inhibitors (compounds 2) involving a cross-metathesis and a Sonogashira coupling reaction as key steps is described.

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.