Functionalization of fluorinated benzenesulfonamides and their inhibitory properties toward carbonic anhydrases

ChemMedChem
Virginija DudutienėDaumantas Matulis

Abstract

Substituted tri- and tetrafluorobenzenesulfonamides were designed, synthesized, and evaluated as high-affinity and isoform-selective carbonic anhydrase (CA) inhibitors. Their binding affinities for recombinant human CA I, II, VA, VI, VII, XII, and XIII catalytic domains were determined by fluorescent thermal shift assay, isothermal titration calorimetry, and a stopped-flow CO2 hydration assay. Variation of the substituents at the 2-, 3-, and 4-positions yielded compounds with a broad range of binding affinities and isoform selectivities. Several 2,4-substituted-3,5,6-trifluorobenzenesulfonamides were effective CA XIII inhibitors with high selectivity over off-target CA I and CA II. 3,4-Disubstituted-2,5,6-trifluorobenzenesulfonamides bound CAs with higher affinity than 2,4-disubstituted-3,5,6-trifluorobenzenesulfonamides. Many such fluorinated benzenesulfonamides were found to be nanomolar inhibitors of CA II, CA VII, tumor-associated CA IX and CA XII, and CA XIII. X-ray crystal structures of inhibitors bound in the active sites of several CA isoforms provide structure-activity relationship information for inhibitor binding affinities and selectivity.

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Citations

Jan 26, 2016·Journal of Medicinal Chemistry·Vladimir O TalibovU Helena Danielson
Aug 25, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Justina KazokaitėDaumantas Matulis
Aug 30, 2016·The Journal of Physical Chemistry. B·Zigmantas ToleikisVytautas Petrauskas
Oct 25, 2016·Journal of Biotechnology·Vaida JuozapaitienėDaumantas Matulis
Feb 6, 2017·Analytical Biochemistry·Joana SmirnovienėDaumantas Matulis
Oct 5, 2017·European Biophysics Journal : EBJ·Aurelija MickevičiūtėDaumantas Matulis
Sep 5, 2019·Scientific Reports·Justina KazokaitėDaumantas Matulis
Feb 23, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Alessio NocentiniClaudiu T Supuran
May 5, 2021·ChemistryOpen·Joana SmirnovienėDaumantas Matulis
Jul 31, 2021·European Biophysics Journal : EBJ·Denis BaronasDaumantas Matulis
Feb 22, 2018·Journal of Medicinal Chemistry·Vaida LinkuvienėDaumantas Matulis
Sep 25, 2020·Biophysical Journal·Virginija DudutienėDaumantas Matulis

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