Inhibition of monoamine oxidase by (E)-styrylisatin analogues

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Van der Walt, Elizna M.¹  Milczek, Erika M.²  Malan, Sarel F.¹  Edmondson, Dale E.²  Castagnoli, Neal, Jr.^3,4  Bergh, Jacobus J.¹  Petzer, Jacobus P.¹ 

[1] North West Univ, Sch Pharm, ZA-2520 Potchefstroom, South Africa

[2] Emory Clin, Dept Biochem & Chem, Atlanta, GA 30322 USA

[3] Virginia Tech, Dept Chem, Blacksburg, VA 24061 USA

[4] Edward Via Coll Osteopath Med, Blacksburg, VA 24061 USA

关键词: Monoamine oxidase A;    Monoamine oxidase B;    Reversible inhibitor;    Isatin;    (E)-5-Styrylisatin;    (E)-6-Styrylisatin;   

DOI  :  10.1016/j.bmcl.2009.03.030

来源: Elsevier

【 摘 要 】

Previous studies have shown that (E)-8-(3-chlorostyryl) caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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