Carbonic Anhydrase Inhibitors. Design of Fluorescent Sulfonamides as Probes of Tumor-Associated Carbonic Anhydrase IX That Inhibit Isozyme IX-mediated Acidification of Hypoxic Tumors

J Med Chem. 2005 Jul 28;48(15):4834-41. doi: 10.1021/jm0501073.

Abstract

Sulfonamides inhibit the catalytic activity of carbonic anhydrases (CAs, EC 4.2.1.1), enzymes participating in the regulation of acid-base balance and ion transport in many tissues. Carbonic anhydrase IX (CA IX), a transmembrane isoform with predominant association with tumors and limited distribution in normal tissues, is strongly overexpressed by hypoxia. Hypoxia increases the catalytic performance of CA IX contributing to microenvironmental acidosis, which influences cancer progression and treatment outcome. CA IX represents a target for detection and therapy of hypoxic tumors. Sulfonamide CA IX selective inhibitors accumulate only in hypoxic cells containing CA IX, reversing acidification mediated by this enzyme. The design of fluorescent sulfonamides that preferentially inhibit the activity of CA IX, showing reduced penetration through the plasma membranes and binding to hypoxic cells expressing CA IX, is reported here. These inhibitors represent promising candidates for developing anticancer therapies based on tumor-associated CA isozyme inhibition and offer interesting tools for imaging and further investigation of hypoxic tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / genetics
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors / chemical synthesis*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Carbonic Anhydrases / biosynthesis
  • Carbonic Anhydrases / genetics
  • Catalytic Domain
  • Cell Hypoxia
  • Cell Line
  • Cell Membrane Permeability
  • Dogs
  • Erythrocyte Membrane / metabolism
  • Extracellular Fluid / metabolism
  • Fluorescent Dyes / chemical synthesis*
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacology
  • Humans
  • Hydrogen-Ion Concentration
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors
  • Mutation
  • Sequence Deletion
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Fluorescent Dyes
  • Isoenzymes
  • Sulfonamides
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases