Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 6, Pages 1396-1403Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.12.004
Keywords
Sulfonamide; Carbonic anhydrase; Cyanoacrylamide; Isoform-selective inhibitor
Funding
- 7th FP EU project (Metoxia)
- King Saud University, Riyadh [10-MED1188-02, 11-MED-1874-2]
- Graduate Studies and Scientific Research Agency, Salman bin Abdulaziz University, Alkharj, Saudi Arabia [2.H.33]
- Council of Higher Education of Turkey
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A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogues) have been obtained by reaction of sulfanilamide with ethylcyanoacetate followed by condensation with aromatic/heterocyclic aldehydes, isothiocyanates or diazonium salts. The new compounds have been investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4. 2.1.1), and more specifically against the cytosolic human (h) isoforms hCA I and II, as well as the transmembrane, tumor-associated ones CA IX and XII, which are validated antitumor targets. Most of the new benzenesulfonamides were low nanomolar or subnanomolar CA IX/XII inhibitors whereas they were less effective as inhibitors of CA I and II. The structure-activity relationship for this class of effective CA inhibitors is also discussed. Generally, electron donating groups in the starting aldehyde reagent favored CA IX and XII inhibition, whereas halogeno, methoxy and dimethylamino moieties led to very potent CA XII inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.
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