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Inhibition of steroid-protein interactions by dicyclohexane derivatives

par Rousseau, Guy G;Jacquemyns, Rolin C.F.R.;Sirett, D.A.N. D.A.N.;Huybrechts, Muriel ;De Coen, Jean-Louis ;Quivy, Jacques
Référence Journal of Steroid Biochemistry, 31, 4, page (691-697)
Publication Publié, 1988

Article révisé par les pairs

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Résumé :

Sixteen dicyclohexane derivatives including the parent compound d,l-3,4-bis (4-oxocyclohexyl)-hexane (PRDX) have been synthesized and studied for putative interference with androgen binding to transport proteins, metabolizing enzymes, and receptors from rat tissues. Several of these analogues inhibited competitively the binding of dihydrotestosterone to ABP, the epididymal androgen transport protein. One compound had an affinity for ABP as high as Kd = 70 nM. Some dicyclohexanes also inhibited the aromatase enzyme which catalyses conversion of androgens into estrogens, as well as the NADPH-dependent, particulate form of 3α(β)-hydroxysteroid dehydrogenase, the enzyme that converts dihydrotestosterone into 5α-androstanediol. For both enzymes the inhibition potency Ki of PRDX was about equal to the Km of the substrate. All of these interactions were specific in that they were modulated by single substitutions on the dicyclohexane molecule and they did not occur with other steroid binding proteins such as 5α-reductase and the intracellular androgen receptor. A conformational study showed that dicyclohexanes can assume a 'steroidoid' conformation that differs from the crystal structure and which could account for the specific interactions with the steroid binding sites described here. © 1988.