Dudutienė Virginija, Zubrienė Asta, Smirnov Alexey, Timm David D, Smirnovienė Joana, Kazokaitė Justina, Michailovienė Vilma, Zakšauskas Audrius, Manakova Elena, Gražulis Saulius, Matulis Daumantas
Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius 02241 (Lithuania).
ChemMedChem. 2015 Apr;10(4):662-87. doi: 10.1002/cmdc.201402490. Epub 2015 Mar 10.
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.
设计、合成并评估了取代的三氟和四氟苯磺酰胺作为高亲和力和亚型选择性碳酸酐酶（CA）抑制剂。通过荧光热位移分析、等温滴定量热法和停流二氧化碳水合分析测定了它们对重组人CA I、II、VA、VI、VII、XII和XIII催化结构域的结合亲和力。2-、3-和4-位取代基的变化产生了具有广泛结合亲和力和亚型选择性的化合物。几种2,4-取代的3,5,6-三氟苯磺酰胺是有效的CA XIII抑制剂，对脱靶CA I和CA II具有高选择性。3,4-二取代的2,5,6-三氟苯磺酰胺与CA的结合亲和力高于2,4-二取代的3,5,6-三氟苯磺酰胺。发现许多此类氟化苯磺酰胺是CA II、CA VII、肿瘤相关CA IX和CA XII以及CA XIII的纳摩尔抑制剂。结合在几种CA亚型活性位点的抑制剂的X射线晶体结构为抑制剂的结合亲和力和选择性提供了构效关系信息。
