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Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties.

Abstract
A series of benzenesulfonamide derivatives incorporating triazine moieties in their molecules was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide, or 4-aminoethylbenzenesulfonamide. The dichlorotriazinyl-benzenesulfonamides intermediates were subsequently derivatized by reaction with various nucleophiles, such as water, methylamine, or aliphatic alcohols (methanol and ethanol). The library of sulfonamides incorporating triazinyl moieties was tested for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumor-associated hCA IX. The new compounds reported here inhibited hCA I with K(I)s in the range of 75-136nM, hCA II with K(I)s in the range of 13-278nM, and hCA IX with K(I)s in the range of 0.12-549nM. The first hCA IX-selective inhibitors were thus detected, as the chlorotriazinyl-sulfanilamide and the bis-ethoxytriazinyl derivatives of sulfanilamide/homosulfanilamide showed selectivity ratios for CA IX over CA II inhibition in the range of 166-706. Furthermore, some of these compounds have subnanomolar affinity for hCA IX, with K(I)s in the range 0.12-0.34nM. These derivatives are interesting candidates for the development of novel unconventional anticancer strategies targeting the hypoxic areas of tumors. Clear renal cell carcinoma, which is the most lethal urologic malignancy and is both characterized by very high CA IX expression and chemotherapy unresponsiveness, could be the leading candidate of such novel therapies.
AuthorsVladimir Garaj, Luca Puccetti, Giuseppe Fasolis, Jean-Yves Winum, Jean-Louis Montero, Andrea Scozzafava, Daniela Vullo, Alessio Innocenti, Claudiu T Supuran
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 14 Issue 21 Pg. 5427-33 (Nov 01 2004) ISSN: 0960-894X [Print] England
PMID15454239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Enzyme Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Triazines
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
Topics
  • Antigens, Neoplasm (chemistry)
  • Antineoplastic Agents (chemical synthesis, chemistry)
  • Carbonic Anhydrase I (antagonists & inhibitors, chemistry)
  • Carbonic Anhydrase II (antagonists & inhibitors, chemistry)
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry)
  • Carbonic Anhydrases (chemistry)
  • Cytosol (enzymology)
  • Enzyme Inhibitors (chemical synthesis, chemistry)
  • Humans
  • Isoenzymes (antagonists & inhibitors, chemistry)
  • Structure-Activity Relationship
  • Sulfonamides (chemical synthesis, chemistry)
  • Triazines (chemical synthesis, chemistry)

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