Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II
Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II(488 views) Di Fiore A, De Simone G, Menchise V, Pedone C, Casini A, Scozzafava A, Supuran CT
Bioorg Med Chem Lett Bioorganic And Medicinal Chemistry Letters (ISSN: 0960-894x), 2005 Apr 1; 15(7): 1937-1942.
Keywords: Benzenesulfonamide Derivative, Carbonate Dehydratase, Carbonate Dehydratase Ii, Carbonate Dehydratase Inhibitor, N 1 (4 Sulfamoylphenyl) N 4 Pentafluorophenylthiosemicarbazide, Nitrogen Derivative, Unclassified Drug, Zinc Ion, Amino Acid Sequence, Article, Crystal Structure, Drug Activity, Drug Mechanism, Drug Protein Binding, Drug Screening, Drug Synthesis, Enzyme Active Site, Hydrogen Bond, Hydrophobicity, Reaction Analysis, Sequence Analysis, X Ray Crystallography, Animals, Binding Sites, Carbonic Anhydrase Ii, Carbonic Anhydrase Inhibitors, X-Ray, Fluorobenzenes, Hydrogen Bonding, Isoenzymes, Phenols, Structure-Activity Relationship, Thiourea,
Affiliations: *** IBB - CNR ***
Dipto. Chim. Biol.-Sezione B., Ist. Biostrutture e Bioimmagini-CNR, University of Naples 'Federico II', via Mezzocannone 16, 80134 Naples, Italy
Univ. degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy
Dipto. Chim. Biol. -Sezione B., Ist. Biostrutture e Bioimmagini-CNR, University of Naples 'Federico II', via Mezzocannone 16, 80134 Naples, Italy
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Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II
N-1-(4-Sulfamoylphenyl)-N-4-pentafluorophenyl-thiosemicarbazide was prepared by the reaction of 4-isothiocyanato-benzenesulfonamide with pentafluorophenyl hydrazine, and proved to be an effective inhibitor of several isozymes of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), such as CA I, II, and IX. Against the physiologically relevant isozymes hCA II and hCA IX, the compound showed inhibition constants in the range of 15-19 nM, whereas it was less effective as a hCA I inhibitor (K-I of 78 nM). The high-resolution X-ray crystal structure of its adduct with hCA 11 showed the inhibitor to bind within the hydrophobic half of the enzyme active site, making extensive and strong van der Waals contacts with amino acid residues Gln92, Val121 Phel31, Leu198, Thr200, Pro202, in addition to the coordination of the sulfonamide nitrogen to the Zn(II) ion of the active site, and participation of the SO2NH2 group to a network of hydrogen bonds involving residues Thr199 and Glu106. These results are helpful for the design of better CA II or CA IX inhibitors based on the thioureido-benzenesulfonamide motif, with potential applications as anti-glaucoma or anti-cancer drugs. (c) 2005 Elsevier Ltd. All rights reserved.
Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II
No results.
Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II