Carbonic anhydrase inhibitors: inhibition of cytosolic/tumor-associated isoforms I, II, and IX with iminodiacetic carboxylates/hydroxamates also incorporating benzenesulfonamide moieties

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1538-43. doi: 10.1016/j.bmcl.2006.12.107. Epub 2007 Jan 8.

Abstract

The synthesis of a new class of sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs), also possessing carboxylate/hydroxamate moieties in their molecule, is reported. These compounds may act on dual antitumor targets, the tumor-associated CA isozymes (CA IX) and some matrix metalloproteinases (MMPs). The compounds were prepared by an original method starting from iminodiacetic acid, and assayed as inhibitors of three isozymes, hCA I, II (cytosolic), and IX (transmembrane). The new derivatives showed weak inhibitory activity against isozyme I (K(I)s in the range of 95-8300 nM), were excellent to moderate CA II inhibitors (K(I)s in the range of 8.4-65 nM), and very good and selective CA IX inhibitors (K(I)s in the range of 3.8-26 nM). The primary sulfonamide moiety is a better zinc-binding group in the design of CAIs as compared to the carboxylate/hydroxamate one, but the presence of hydroxamate functionalities in the molecule of CAIs leads to selectivity for the tumor-associated isozyme IX over the ubiquitous, cytosolic isoform II.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cell Membrane / enzymology
  • Cytosol / drug effects
  • Cytosol / enzymology*
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / pharmacology*
  • Indicators and Reagents
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / enzymology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Hydroxamic Acids
  • Indicators and Reagents
  • Isoenzymes
  • Sulfonamides