期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 17, 期 6, 页码 1538-1543出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2006.12.107
关键词
carbonic anhydrase; cytosolic isozyme; tumor-associated isozyme IX; sulfonamide; hydroxamate; carboxylate; zinc-binding function
The synthesis of a new class of sulfonamide carbonic anhydrase (CA, EC 4.2. 1. 1) inhibitors (CAIs), also possessing carboxylate/hydroxamate moieties in their molecule, is reported. These compounds may act on dual antitumor targets, the tumor-associated CA isozymes (CA IX) and some matrix metalloproteinases (MMPs). The compounds were prepared by an original method starting from iminodiacetic acid, and assayed as inhibitors of three isozymes, hCA I, II (cytosolic), and IX (transmembrane). The new derivatives showed weak inhibitory activity against isozyme I (K(I)s in the range of 95-8300 nM), were excellent to moderate CA II inhibitors (K(I)s in the range of 8.4-65 nM), and very good and selective CA IX inhibitors (Kis in the range of 3.8-26 nM). The primary sulfonamide moiety is a better zinc-binding group in the design of CAls as compared to the carboxylate/hydroxamate one, but the presence of hydroxamate functionalities in the molecule of CAls leads to selectivity for the tumor-associated isozyme IX over the ubiquitous, cytosolic isoform II. (c) 2007 Elsevier Ltd. All rights reserved.
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