Author： Bérubé Marie Poirier Donald
Publisher： Informa Healthcare
ISSN： 1475-6366
Source： Journal of Enzyme Inhibition and Medicinal Chemistry, Vol.24, Iss.3, 2009-06, pp. : 832-843
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Abstract
Endocrine therapies are widely used for the treatment of estrogen-sensitive diseases. 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the last step of the biosynthesis of potent estrogen estradiol (E2). This enzyme catalyzes the reduction of the C17-ketosteroid estrone (E1) into the C17β-hydroxy steroid E2 using the cofactor NAD(P)H. The X-ray analysis of E2/adenosine bisubstrate inhibitor EM-1745 proven that this compound interacts with both the substrate- and the cofactor-binding sites. However, E1 is a better substrate of 17β-HSD1 than E2. 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 (IC50 = 12 nM) than the C17-alcohol (IC50 = 4 nM) in homogenated HEK-293 cells overexpressing 17β-HSD1. Our results contribute to the knowledge of an unexpected observation: the C17-ketone steroidal inhibitors of 17β-HSD1 are less potent than their corresponding C17-alcohol derivatives.
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