Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Kumar, G. D. Kishore¹  Chavarria, Gustavo E.¹  Charlton-Sevcik, Amanda K.¹  Arispe, Wara M.¹  MacDonough, Matthew T.¹  Strecker, Tracy E.¹  Chen, Shen-En¹  Siim, Bronwyn G.²  Chaplin, David J.²  Trawick, Mary Lynn¹  Pinney, Kevin G.¹ 

[1] Baylor Univ, Dept Chem & Biochem, Waco, TX 76798 USA

[2] OXiGENE Inc, Magdalen Ctr, Oxford Sci Pk, Oxford OX4 4GA, England

关键词: Inhibitors of cathepsin L;    Inhibitors of cathepsin B;    Chemical synthesis;    Molecular design;    Molecular modeling;   

DOI  :  10.1016/j.bmcl.2009.12.090

来源: Elsevier

【 摘 要 】

A small library of 36 functionalized benzophenone thiosemicarbazone analogs has been prepared by chemical synthesis and evaluated for their ability to inhibit the cysteine proteases cathepsin L and cathepsin B. Inhibitors of cathepsins L and B have the potential to limit or arrest cancer metastasis. The six most active inhibitors of cathepsin L (IC50 < 85 nM) in this series incorporate a meta-bromo sub-stituent in one aryl ring along with a variety of functional groups in the second aryl ring. These six analogs are selective for their inhibition of cathepsin L versus cathepsin B (IC50 > 10,000 nM). The most active analog in the series, 3-bromophenyl-2'-fluorophenyl thiosemicarbazone 1, also efficiently inhibits cell invasion of the DU-145 human prostate cancer cell line. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free