Abstract：
:A series of steroidal and nonsteroidal Michael acceptors that represent reaction products for 3 alpha-hydroxysteroid dehydrogenase were synthesized and evaluated as potential enzyme-generated inactivators. Introduction of exocyclic olefins either at C-2 or C-6 produced inhibitors with high affinity for the enzyme (0.05 to 5.0 microM). However, despite this affinity, none of these compounds produced time-dependent inactivation of the enzyme. By contrast, analogs based on 1-phenyl-2-propen-1-one were stoichiometric inactivators of the enzyme and ease of turnover of the parent latent Michael acceptor depended on the presence of an electron-withdrawing substituent at the para position. A series of steroidal and nonsteroidal epoxides in which the oxiranyl oxygen could be substituted for the 3-ketone (the acceptor carbonyl of a steroid substrate) were also synthesized and evaluated as potential mechanism-based inactivators. Steroidal 2 alpha,3 alpha-, and 3 alpha,4 alpha-epoxides as well as 3 alpha- and 3 beta-spiroepoxides did not bind to the enzyme and were unable to cause enzyme inactivation in either the presence or absence of pyridine nucleotide. In contrast, nitrostyrene oxides produced time-dependent inactivation, the rate of which was governed by the presence of an electron withdrawing group at the para position. These data indicate that the design of mechanism-based inactivators for 3 alpha-hydroxysteroid dehydrogenase requires the incorporation of electron-withdrawing groups adjacent to the latent enzyme-activated group and, as a result, the turnover and/or reactivity of these compounds is increased. Moreover, these compounds can be modeled on nonsteroids.
journal_name
Steroidsjournal_title
Steroidsauthors
Penning TM,Thronton R,Ricigliano JWdoi
10.1016/0039-128x(91)90030-ysubject
Has Abstractpub_date
1991-08-01 00:00:00pages
420-7issue
8eissn
0039-128Xissn
1878-5867pii
0039-128X(91)90030-Yjournal_volume
56pub_type
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