Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: Solution and crystallographic investigations

Jason Wagner, Balendu Sankara Avvaru, Arthur H. Robbins, Andrea Scozzafava, Claudiu T. Supuran, Robert McKenna

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

We investigated a series of coumarinyl-substituted aromatic sulfonamides as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medical applications, the cytosolic hCA I, and II, and the transmembrane, tumor-associated hCA IX and XII. Compounds incorporating 7-methoxy-coumarin-4- yl-acetamide-tails and benzenesulfonamide and benzene-1,3-disulfonamide scaffolds showed medium potency inhibition of hCA I (K Is of 73-131 nM), effective hCA II inhibition (K Is of 9.1-36 nM) and less effective hCA IX and XII inhibition (K Is of 55-128 nM). Only one compound, the derivatized 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide with the coumarinyl tail, showed effective inhibition of the transmembrane isoforms, with K Is of 5.9-14.2 nM, although it was less effective as hCA I and II inhibitor (K Is of 36-120 nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)- benzenesulfonamide (K I of 9.1 nM against hCA II) showed the intact inhibitor coordinated to the zinc ion from the enzyme active site by the sulfonamide moiety, and participating in a edge-to-face stacking with Phe131, in addition to other hydrophobic and hydrophilic interactions with water molecules and amino acid residues from the active site. Thus, sulfonamides incorporating coumarin rings have a distinct inhibition mechanism compared to the coumarins, and may lead to compounds with interesting inhibition profiles against various α-CAs found in mammals or parasites, such as Plasmodium falciparum.

Original languageEnglish (US)
Pages (from-to)4873-4878
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number14
DOIs
StatePublished - Jul 15 2010
Externally publishedYes

Keywords

  • Carbonic anhydrase
  • Coumarinyl-substituted sulfonamides
  • Inhibition mechanism
  • Isoformselective inhibitor
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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