Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms i and II: Solution and X-ray crystallographic studies

Fabrizio Carta, Vladimir Garaj, Alfonso Maresca, Jason Wagner, Balendu Sankara Avvaru, Arthur H. Robbins, Andrea Scozzafava, Robert McKenna, Claudiu T. Supuran

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Reaction of cyanuryl chloride with d,l-amino acids and amino alcohols afforded a new series of triazinyl-substituted benzenesulfonamides incorporating amino acyl/hydroxyalkyl-amino moieties. Inhibition studies of physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA I, II, IX, XII and XIV with these compounds are reported. They showed moderate-weak inhibition of the cytosolic, offtarget isozymes CA I and II, but many of them were low nanomolar inhibitors of the transmembrane, tumor-associated CA IX and XII (and also of CA XIV). The X-ray crystal structure of two of these compounds in adduct with CA II allowed us to understand the features associated with this strong inhibitory properties and possibly also their selectivity. Two of these compounds were also investigated for the inhibition of other human isoforms, that is, hCA IV, VA, VB, VI, VII and XIII, as well as inhibitors of the fungal pathogenic CAs Nce103 (Candida albicans) and Can2 (Cryptococcus neoformans), showing interesting activity. The 1,3,5-triazinyl-substituted benzenesulfonamides constitute thus a class of compounds with great potential for obtaining inhibitors targeting both α-class mammalian, tumor-associated, and β-class from pathogenic organisms CAs.

Original languageEnglish (US)
Pages (from-to)3105-3119
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number10
DOIs
StatePublished - May 15 2011
Externally publishedYes

Keywords

  • 1,3,5-Triazine
  • Carbonic anhydrase
  • Isoform IX, XII
  • Isoform-selective inhibitor
  • Sulfonamide
  • X-ray crystallography

ASJC Scopus subject areas

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

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