Coumarin-pyrazoline Hybrids as Selective Inhibitors of the Tumor-associated Carbonic Anhydrase IX and XII

Author(s):

Aditi Redij, Simone Carradori*, Andrea Petreni, Claudiu T. Supuran and Mrunmayee P. Toraskar*   Pages 1217 - 1223 ( 7 )

Abstract:

<P>Aim: Human carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are validated antitumor/ antimetastatic drug and tumor imaging targets with sulfonamide inhibitors and monoclonal antibodies in clinical development. Coumarins act as isoform-selective inhibitors of these isoforms over the cytosolic and mitochondrial ones. <P> Methods: We report the synthesis and in vitro CA inhibitory evaluation of a large panel of coumarins incorporating pyrazole-1-carboxamide moieties. Compounds were fully characterized before the assessment of their inhibitory activity. A stopped-flow CO₂ hydrase assay was performed for the biological test. <P> Results: These coumarins did not inhibit the widespread, off-target isoforms CA I and II (K_I >50 μM), but they were sub-micromolar CA IX/XII inhibitors with an interesting selectivity index higher than the reference compound. Selectivity between α- and &#946;-class of CAs was also promising. <P> Conclusion: These compounds may be used as leads for the rational design and development of non-sulfonamide CA IX/XII effective inhibitors.</P>

Keywords:

Carbonic anhydrase, hCA IX, hCA XII, antitumor, coumarin, pyrazole-1-carboxamides.

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