title: Functionalization of fluorinated benzenesulfonamides and their inhibitory properties toward carbonic anhydrases.
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.
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius 02241 (Lithuania).
authors.forename: Virginija
authors.initials: V
authors.lastname: Dudutienė
authors.forename: Asta
authors.initials: A
authors.lastname: Zubrienė
authors.forename: Alexey
authors.initials: A
authors.lastname: Smirnov
authors.forename: David D
authors.initials: DD
authors.lastname: Timm
authors.forename: Joana
authors.initials: J
authors.lastname: Smirnovienė
authors.forename: Justina
authors.initials: J
authors.lastname: Kazokaitė
authors.forename: Vilma
authors.initials: V
authors.lastname: Michailovienė
authors.forename: Audrius
authors.initials: A
authors.lastname: Zakšauskas
authors.forename: Elena
authors.initials: E
authors.lastname: Manakova
authors.forename: Saulius
authors.initials: S
authors.lastname: Gražulis
authors.forename: Daumantas
authors.initials: D
authors.lastname: Matulis
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: X-ray crystallography; carbonic anhydrases; fluorescent thermal shift assay; fluorinated benzenesulfonamides; isothermal titration calorimetry; thermofluor