Synthesis and biological evaluation of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core.

Many breast tumors are hormone-dependent, and estrogens, especially estradiol (E2), have a pivotal role in their growth and development. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of female sex steroids, catalyzing the NADPH-dependent reduction of estrone into biologically active estradiol. In this study, a library of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-one based compounds was synthesized, and the biological activities against 17beta-HSD1 in a cell-free and in a cell-based assay were evaluated.

Pharmacophore modelling of 17beta-HSD1 enzyme based on active inhibitors and enzyme structure.

The 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) enzyme regulates the conversion of estrone (E1) to the biologically active estradiol (E2). Due to its role as a key enzyme in female hormone production, it has emerged as an attractive drug target for inhibitor development in relation to hormone-dependent breast cancer. Herein, we report four pharmacophore models of 17beta-HSD1 based on a crystal structure, a relaxed crystal structure, a library of 17beta-HSD1 inhibitors and on a docked complex of 17betaHSD1 enzyme and a potent inhibitor.

Active site analysis of 17beta-hydroxysteroid dehydrogenase type 1 enzyme complexes with SPROUT.

Estrogens, especially estradiol, have been shown to stimulate the proliferation of hormone-dependent types of breast cancer cells. 17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) enzyme catalyses the synthesis of the active female estrogen, estradiol and is thus an attractive target for structure-based ligand design for the prevention and control of breast tumour growth. In this study, the active site of 17beta-HSD1 has been reviewed, and three crystal structure complexes (estradiol/NADP+, equilin/NADP+, dehydroepiandrosterone) of 17beta-HSD1 have been selected to be analysed for de novo ligand design.