Authors: Bérubé, Marie; Poirier, Donald

Source: Canadian Journal of Chemistry, Volume 87, Number 8, August 2009 , pp. 1180-1199(20)

Publisher: NRC Research Press

Abstract:

A series of estradiol (E₂) derivatives were designed to interact with both the substrate- and the cofactor-binding sites of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). These analogues of potent E₂-adenosine hybrid inhibitor EM-1745, where the adenosine moiety was replaced by a more stable benzene derivative, were synthesized from estrone using alkene cross-metathesis and Sonogashira coupling reactions as key steps. In vitro biological evaluation of these steroid derivatives revealed that a spacer of 13 methylenes, between the 16β-position of E₂ and the adenosine mimic bearing a carboxylic acid group, gave the best inhibition of 17β-HSD1.

Plusieurs dérivés de l'estradiol (E₂) ont été préparés pour interagir avec le site de liaison du substrat et le site de liaison du cofacteur de la 17β-hydroxystéroïde déshydrogénase type 1 (17β-HSD1). Ces analogues du puissant inhibiteur EM-1745, un hybride E₂-adénosine dont la partie adénosine a été remplacée par un dérivé benzylique plus stable, ont été obtenus à partir de l'estrone en utilisant la métathèse de Grubbs et le couplage de Sonogashira comme étapes clé. L'évaluation biologique in vitro de ces dérivés stéroïdiens a montré qu'une chaîne ayant 13 groupes méthylènes, entre la position 16β du stéroïde E₂ et le noyau benzylique porteur d'un acide carboxylique, provoquait la meilleure inhibition de l'enzyme 17β-HSD1.

Document Type: Research article

Publication date: 2009-08-01

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