Synthesis of alkyne- and azide-functionalised aziridine and epoxide carbocycles for development of selective glucuronidase mechanism-based inhibitors

Heparanase (HPSE) is an endo-acting beta-glucuronidase and the only known enzyme responsible for the regulation of extracellular heparan sulfate (HS) structures, a glycosaminoglycan (GAG) occurring in conjugation with a protein class called heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM). The enzyme is found to be significantly upregulated in aggressive cancer types aiding cell proliferation by increased degradation of HS. Inhibition of HPSE reduces cancer growth making it an interesting druggable target for cancer treatment and diagnostics. Only few of the known efficient HPSE inhibitors have progressed through clinical studies and none of them has been approved yet. We here present the synthesis of three cyclophellitol scaffolds, based on known mechanism-based inhibitors of HSPE. These novel scaffolds are amenable to facile elaboration via copper-catalysed azide-alkyne cycloadditions to aid in exploring the structure-activity relationship for selective inhibitors of HSPE.