Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
Bioorg Med Chem Lett. 2011 Oct 15;21(20):6058-61. doi: 10.1016/j.bmcl.2011.08.066. Epub 2011 Aug 22.
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.
碳酸酐酶 9（CAIX）是开发新型癌症治疗方法的最新验证靶标。在这封信中，我们描述了一系列新型基于碳水化合物的 1,5-二取代-1,2,3-三唑苯磺酰胺的合成和 CA 抑制作用。我们合成的关键步骤是使用钌催化的叠氮-炔环加成（RuAAC），从碳水化合物叠氮化物底物和 4-乙炔基苯磺酰胺中进行区域选择性的 Huisgen 1,3-偶极环加成（1,3-DCR）。我们的研究结果确定了一些三唑抑制剂（化合物 18、19、21-23 和 26），它们的抑制常数小于 10 nM，可阻断 CAIX 的活性。一种抑制剂（化合物 17）对 CAIX 具有非常好的选择性，而对脱靶 CA 则没有选择性。这些 CA 抑制剂具有开发潜力，可以选择性地靶向癌细胞，导致细胞死亡。
