Superacid synthesis of halogen containing N-substituted-4-aminobenzene sulfonamides: new selective tumor-associated carbonic anhydrase inhibitors

Guillaume Compain; Agnès Martin-Mingot; Alfonso Maresca; Sebastien Thibaudeau; Claudiu T Supuran

doi:10.1016/j.bmc.2012.05.037

Superacid synthesis of halogen containing N-substituted-4-aminobenzene sulfonamides: new selective tumor-associated carbonic anhydrase inhibitors

Bioorg Med Chem. 2013 Mar 15;21(6):1555-63. doi: 10.1016/j.bmc.2012.05.037. Epub 2012 May 26.

Authors

Guillaume Compain¹, Agnès Martin-Mingot, Alfonso Maresca, Sebastien Thibaudeau, Claudiu T Supuran

Affiliation

¹ Superacid group in « Glycochimie, Superacide et Chimie des systèmes » team-Université de Poitiers, CNRS UMR 7285 IC2MP, 4, avenue Michel Brunet, F-86022 Poitiers Cedex, France.

PMID: 22705188
DOI: 10.1016/j.bmc.2012.05.037

Abstract

A series of new, halogen containing N-substituted 4-aminobenzenesulfonamides were synthesized by using superacid HF/SbF5 chemistry and investigated as inhibitors of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, that is, the cytosolic hCA I and II and, the tumor-associated transmembrane isoforms hCA IX and XII. Despite the substitution of the sulfonamide function, the presence of fluorine atom(s) in β position of the sulfonamide function strongly favors hCA inhibition. A similar effect of the β-fluorinated alkyl substitution on the amino function has been also observed. Among the tested compounds, several chlorinated derivatives have been identified as selective nanomolar, tumor-associated isoforms inhibitors. These non-primary sulfonamides probably bind in the coumarin-binding site, at the entrance of the cavity, and not to the metal ion as the primary sulfonamide inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm / chemistry*
Antigens, Neoplasm / metabolism
Binding Sites
Carbonic Anhydrase I / chemistry
Carbonic Anhydrase I / metabolism
Carbonic Anhydrase II / chemistry
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemical synthesis*
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Catalytic Domain
Fluorine / chemistry*
Humans
Molecular Docking Simulation
Neoplasms / enzymology
Neoplasms / metabolism
Neoplasms / pathology
Protein Binding
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / metabolism

Substances

Antigens, Neoplasm
Carbonic Anhydrase Inhibitors
Sulfonamides
Fluorine
Carbonic Anhydrase I
Carbonic Anhydrase II
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII