Alkyne‐ and Azide‐Functionalised Cyclophellitol Derivatives for Selective Glucuronidase Targeting

Abstract Heparanase is an endo‐acting β‐glucuronidase responsible for the degradation of heparan sulfate structures in the extracellular matrix. The enzyme is found to be significantly upregulated in aggressive cancer types, aiding cell proliferation by liberation of growth factors, increasing angiogenesis and metastasis. Despite much interest in the development of inhibitors to control this activity, no compound targeting heparanase has yet been approved as a drug. While mechanism‐based inhibitors derived from the natural product cyclophellitol are very potent enzyme inactivators through their reactive epoxide, one challenge in their development is in achieving selectivity for heparanase over related glycosidases while also maintaining a balance of appropriate pharmacological properties. We present here the synthesis of three cyclophellitol scaffolds presenting azide and alkyne handles at key positions, which are amenable to facile elaboration via copper‐catalysed azide‐alkyne cycloadditions to aid in exploring the structure‐activity relationship for selective inhibitors of heparanase.