Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX

F Abbate, A Casini, T Owa*, A Scozzafava, CT Supuran

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

248 Citations (Scopus)

Abstract

E7070 [N-(w3-chloro-7-indolyl)-1,4-benzenedisulfonamide] is an anticancer drug candidate under clinical development for the treatment of several types of cancers. We prove here that this compound also acts as a potent carbonic anhydrase (CA) inhibitor. Similarly to the clinically used drugs acetazolamide, methazolamide and topiramate, E7070 showed inhibition constants in the range of 15-31 nM against isozymes I, II and IX, being slightly less effective as a CA IV inhibitor (K-i of 65 nM). The X-ray crystal structure of the adduct of hCA II with E7070 revealed unprecedented interactions between the inhibitor and the active site, with three different conformations of the chloroindole fragment of the inhibitor interacting with different amino acid residues/water molecules of the enzyme. A superimposition of these conformations with those of other sulfonamide/sulfamate CA inhibitors indicated that similar regions of the hCA II active site could be involved in the interaction with inhibitors. (C) 2003 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)217-223
Number of pages7
JournalBioorganic & Medicinal Chemistry Letters
Volume14
Issue number1
DOIs
Publication statusPublished - 5-Jan-2004
Externally publishedYes

Keywords

  • RAY CRYSTALLOGRAPHIC STRUCTURE
  • CELL-CYCLE PROGRESSION
  • CANCER CELLS
  • DRUG DESIGN
  • PHASE-I
  • DERIVATIVES
  • EXPRESSION
  • ADDUCT
  • VITRO

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