Synthesis of glycoconjugate carbonic anhydrase inhibitors by ruthenium-catalysed azide-alkyne 1,3-dipolar cycloaddition

Carbonic anhydrase IX (CA IX) is a recently validated target for the development of new cancer therapies. In this Letter we describe the synthesis and CA inhibition of a novel series of carbohydrate-based 1,5-disubstituted-1,2,3-triazole benzenesulfonamides. The key step of our synthesis is the regioselective Huisgen’s 1,3-dipolar cycloaddition reaction (1,3-DCR) from carbohydrate azide substrates and 4-ethynylbenzenesulfonamide using a ruthenium-catalysed azide-alkyne cycloaddition (RuAAC). Our findings identified a number of triazole inhibitors (compounds 18, 19, 21–23, and 26) that block CA IX activity with inhibition constants less than 10 nM. One inhibitor (compound 17) possessed very good selectivity for CA IX over off-target CAs. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.

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