期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 8, 页码 2216-2219出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.03.004
关键词
Inhibitor; Cholesterol; Metabolism; Degradation; Pathogen; Tuberculosis; Steroid
资金
- National Institutes of Health [AI065251, HL53306]
- New York State Technology and Research Program [FDP C040076]
- DOE-GAANN
The cholesterol metabolism pathway in Mycobacterium tuberculosis (M. tb) is a potential source of energy as well as secondary metabolite production that is important for survival of M. tb in the host macrophage. Oxidation and isomerization of 3 beta-hydroxysterols to 4-en-3-ones is requisite for sterol metabolism and the reaction is catalyzed by 3 beta-hydroxysteroid dehydrogenase (Rv1106c). Three series of 6-azasteroids and 4-azasteroids were employed to define the substrate preferences of M. tb 3 beta-hydroxysteroid dehydrogenase. 6-Azasteroids with large, hydrophobic side chains at the C17 position are the most effective inhibitors. Substitutions at C1, C2, C4 and N6 were poorly tolerated. Our structure-activity studies indicate that the 6-aza version of cholesterol is the best and tightest binding competitive inhibitor (K-i = 100 nM) of the steroid substrate and are consistent with cholesterol being the preferred substrate of M. tb 3 beta-hydroxysteroid dehydrogenase. (C) 2011 Elsevier Ltd. All rights reserved.
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