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

Abstract

Endocrine therapies are widely used for the treatment of estrogen-sensitive diseases. 17b-hydroxysteroid dehydrogenase type 1 (17b-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 C17b-hydroxy steroid E 2 using the cofactor NAD(P)H. The X-ray analysis of E 2 /adenosine bisubstrate inhibitor EM-1745 proven that this compound interacts with both the substrate-and the cofactor-binding sites. However, E 1 is a better substrate of 17b-HSD1 than E 2 . Thus, in order to improve the inhibitory potency of EM-1745, the C17-ketone analogue was prepared. During this work, a new and more efficient method for synthesizing EM-1745 was developed using an esterification and a cross-metathesis as key steps. Contrary to what was expected, the C17-ketone analogue of EM-1745 is a less potent inhibitor (IC 50 ¼ 12 nM) than the C17-alcohol (IC 50 ¼ 4 nM) in homogenated HEK-293 cells overexpressing 17b-HSD1. Our results contribute to the knowledge of an unexpected observation: the C17-ketone steroidal inhibitors of 17b-HSD1 are less potent than their corresponding C17-alcohol derivatives.

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

“…By synthesizing and testing analogues of 32 having no adenosine moiety (compounds 35-40) or no E2 nucleus (compound 41), it was clearly demonstrated that both components (E2 and adenosine) are crucial for inhibitory activity [51]. A new and more efficient synthesis of 32 as well as its C17-ketone analogue 42 was next reported and, contrary to what was expected, the C17-ketone 42 was a less (3 times) potent inhibitor than the C17-alcohol 32 [53]. The mode of inhibition and K i value of the most efficient hybrid inhibitor was further studied.…”

Steroid Conjugates as Potential Anti-Cancer Agents

“…В рамках этих исследований был осуществлен синтез конъюгатов 145 и 146 (рис. 16а), объединяющих в составе 1 молекулы и субстрат, и фрагмент кофактора [90,91].…”

Synthesis and Biological Evaluation of Triazolyl 13α-Estrone–Nucleoside Bioconjugates

“…The connection types applied in the nucleoside–steroid conjugates prepared so far are generally ester bonds [26,28,29,30,31]. On the other hand, in case of conjugates of polyfunctional biomolecules, the CuAAC method is a widely used alternative [32,33] which forms a stable 1,2,3-triazole ring.…”