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Synthesis of 6-tetrazolyl-substituted sulfocoumarins acting as highly potent and selective inhibitors of the tumor-associated carbonic anhydrase isoforms IX and XII.

Abstract
A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3,4-tetrazol-5-yl moieties were synthesized by reaction of 6-iodo-sulfocoumarin and the corresponding tetrazole via the CH activation reaction. The new sulfocoumarins incorporating alkyl and substituted aryl moieties at the 1-position of the tetrazole, were investigated for the inhibition of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, the cytosolic hCA I and II; and the transmembrane, tumor-associated hCA IX and XII. The tetrazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms (KIs >10 μM) but showed effective inhibition against the two transmembrane CAs, with KIs ranging from 6.5 to 68.6 nM against hCA IX, and between 4.3 and 59.8 nM against hCA XII. As hCA IX and XII are validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here, may be useful for identifying suitable drug candidates for clinical trials.
AuthorsAiga Grandane, Muhammet Tanc, Raivis Zalubovskis, Claudiu T Supuran
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 5 Pg. 1522-8 (Mar 01 2014) ISSN: 1464-3391 [Electronic] England
PMID24513186 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Antigens, Neoplasm
  • Carbonic Anhydrase Inhibitors
  • Sulfonamides
  • Triazoles
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • Carbonic Anhydrases
Topics
  • Antigens, Neoplasm
  • Carbonic Anhydrase I (antagonists & inhibitors, chemistry, metabolism)
  • Carbonic Anhydrase II (antagonists & inhibitors, chemistry, metabolism)
  • Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Carbonic Anhydrases (chemistry, metabolism)
  • Enzyme Activation (drug effects)
  • Humans
  • Neoplasms (enzymology, pathology)
  • Protein Binding
  • Structure-Activity Relationship
  • Sulfonamides (pharmacology)
  • Triazoles (chemistry)

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