Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII
| Autor: | Miglė Kišonaitė, Sigitas Tumkevicius, Elena Manakova, Asta Zubrienė, Edita Čapkauskaitė, Vilma Michailovienė, Alexey Smirnov, Jolanta Torresan, Daumantas Matulis, Justina Kazokaitė, Saulius Gražulis, Vaida Jogaitė, Joana Gylytė |
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| Rok vydání: | 2013 |
| Předmět: |
Gene isoform
Thermal shift assay Pyrimidine Stereochemistry Clinical Biochemistry Pharmaceutical Science Calorimetry Crystallography X-Ray 01 natural sciences Biochemistry law.invention 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship law Drug Discovery Moiety Humans Carbonic Anhydrase Inhibitors Molecular Biology 030304 developmental biology Carbonic Anhydrases 0303 health sciences Sulfonamides Binding Sites 010405 organic chemistry Organic Chemistry Isothermal titration calorimetry Affinities Recombinant Proteins 0104 chemical sciences 3. Good health Protein Structure Tertiary Enzyme Activation Isoenzymes Kinetics Pyrimidines chemistry Recombinant DNA Molecular Medicine Selectivity Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry. 21(22) |
| ISSN: | 1464-3391 |
| Popis: | 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 CO 2 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. |
| Databáze: | OpenAIRE |
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