Synthesis and Evaluation of Amido-Deoxyestradiol Derivatives as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 12

Siham      Farhane; Michelle-Audrey      Fournier; Donald      Poirier

Abstract

Estrogens are known to be an important factor in the development of estrogen-sensitive diseases. Among the enzymes involved in the biosynthesis of steroid hormones, 17β-hydroxysteroid dehydrogenase type 12 (17β-HSD12) is responsible for the reduction of estrone (E1) to estradiol (E2), this later revealed to stimulate the proliferation of estrogensensitive cells. To better understand the role of 17β-HSD12 and to better control the formation of E2 in a therapeutic perspective, we concentrated our work on synthesizing inhibitors. Knowing that a side chain at position 17α and the absence of any functional group at position 3 of E2 are important for inhibitory activity, we generated two series of 17α- amido-3-desoxyestradiol derivatives and measured their potential as inhibitors of 17β-HSD12. Parallel liquid-phase organic synthesis was used to prepare library A (36 compounds), while library B (19 compounds) was generated by direct carbonylation using high density microwave irradiation. The inhibitory results have shown that compounds from library B produced promising inhibition of 17β-HSD12, unlike compounds from library A. Indeed, seven compounds in library B inhibited the enzyme activity (transformation of E1 to E2) by 41-57% and 69-74% at 1 and 10 μM, respectively.

Keywords: 17βHydroxysteroid dehydrogenase, enzyme, inhibitor, steroid, estrone, cancer, chemical synthesis, amination, amidation, estrogens