Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 7, Pages 2093-2106Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.01.008
Keywords
Carbonic anhydrase inhibitors; Isothermal titration calorimetry; Thermal shift assay; ThermoFluor (R); Fluorinated benzenesulfonamide; X-ray crystallography
Funding
- Research Council of Lithuania [MIP-067/2011, VP1-3.1-SMM-01-V-02-003]
- FP7-REGPOT-2009-1 grant 'MoBiLi' [245721]
- COST [TD0905, CM0804]
- European Community [RII3-CT-2004-506008]
- MoBiLi project
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A series of 4-substituted-2,3,5,6-tetrafluorobenezenesulfonamides were synthesized and their binding potencies as inhibitors of recombinant human carbonic anhydrase isozymes I, II, VII, XII, and XIII were determined by the thermal shift assay, isothermal titration calorimetry, and stop-flow CO2 hydration assay. All fluorinated benzenesulfonamides exhibited nanomolar binding potency toward tested CAs and fluorinated benzenesulfonamides posessed higher binding potency than non-fluorinated compounds. The crystal structures of 4-[(4,6-dimethylpyrimidin-2-yl)thio]-2,3,5,6-tetrafluorobenzenesulfonamide in complex with CA II and CA XII, and 2,3,5,6-tetrafluoro-4-[(2-hydroxyethyl)sulfonyl]benzenesulfonamide in complex with CA XIII were determined. The observed dissociation constants for several fluorinated compounds reached subnanomolar range for CA I isozyme. The affinity and the selectivity of the compounds towards tested isozymes are presented. (C) 2013 Elsevier Ltd. All rights reserved.
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