6-Triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrases IX and XII

doi:10.1016/j.bmcl.2014.01.076

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 5, 1 March 2014, Pages 1256-1260

https://doi.org/10.1016/j.bmcl.2014.01.076 Get rights and content

Abstract

A series of 6-substituted sulfocoumarins incorporating substituted-1,2,3-triazol-4-yl-/5-yl moieties were synthesized by employing click chemistry. The new sulfocoumarins incorporated cycloalkyl, tert-butyl and substituted aryl moieties at the triazole ring, and 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 triazole-substituted sulfocoumarins did not inhibit the ubiquitous, off-target cytosolic isoforms hCA I and II (K_Is >10 μM) but showed effective inhibition against the two transmembrane CAs, with K_Is ranging from 7.2 to 10.5 nM against hCA IX, and between 5.5 and 17.7 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.

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Acknowledgments

This work was financed by two FP7 EU grants (METOXIA and DYNANO).

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6-Triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrases IX and XII

Abstract

Graphical abstract

Section snippets

Acknowledgments

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Radiother. Oncol.

Nat. Rev. Drug Disc.

Expert Opin. Ther. Pat.

Expert Opin. Emerg. Drugs

Expert Opin. Drug Discovery

Bioorg. Med. Chem. Lett.

Cancer Res.

Expert Opin. Ther. Pat.

J. Med. Chem.

Expert Opin. Ther. Pat.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

J. Med. Chem.

Chem. Rev.

Nat. Rev. Drug Disc.