Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I,II, VI,VII, XII,and XIII |
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Authors: | Edita Čapkauskaitė Asta Zubrienė Alexey Smirnov Jolanta Torresan Miglė Kišonaitė Justina Kazokaitė Joana Gylytė Vilma Michailovienė Vaida Jogaitė Elena Manakova Saulius Gražulis Sigitas Tumkevičius Daumantas Matulis |
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Affiliation: | 1. Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Grai?iūno 8, Vilnius LT-02241, Lithuania;2. Department of Protein–DNA Interactions, Institute of Biotechnology, Vilnius University, Grai?iūno 8, Vilnius LT-02241, Lithuania;3. Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania |
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Abstract: | Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.1 Systematic structure–activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms. |
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Keywords: | Carbonic anhydrase isozymes Isothermal titration calorimetry Thermal shift assay ThermoFluor® Sulfonamides as CA inhibitors Pyrimidine |
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