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

A Di Fiore, G De Simone*, [No Value] Menchise, C Pedone, A Casini, A Scozzafava, CT Supuran

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)1937-1942
Number of pages6
JournalBioorganic & Medicinal Chemistry Letters
Volume15
Issue number7
DOIs
Publication statusPublished - 1-Apr-2005
Externally publishedYes

Keywords

  • CRYSTALLOGRAPHIC STRUCTURE
  • THERAPEUTIC APPLICATIONS
  • DRUG DESIGN
  • SULFONAMIDES
  • ADDUCT
  • ANTICANCER
  • BINDING
  • CANCER

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