Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 45, Issue 11, Pages 5309-5317Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2010.08.052
Keywords
Aldo-keto reductase; 3-Bromo-5-phenylsalicylic acid; Cancer; Drug design; Human 20 alpha-hydroxysteroid dehydrogenase; Human 3 alpha-hydroxysteroid dehydrogenase
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Funding
- Monash Graduate School
- Grants-in-Aid for Scientific Research [22590102] Funding Source: KAKEN
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The tertiary structure of the Leu308Val mutant of human 20 alpha-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5-substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (K-i = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3 alpha-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC50 value equal to 100 nM. (C) 2010 Elsevier Masson SAS. All rights reserved.
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