Sialyltransferase Inhibitors as Potential Anti-Cancer Agents

Sialic acid occupies a privileged position at the terminus of the glycan chain of many cell-surface glycoconjugates. Owing to both their structure and location, charged sialic acid residues mediate numerous critical interactions in cell-cell communication including cell recognition, invasion, migration, receptor binding, and immunological responses. Sialyltransferases (STs) are the enzymes involved in the biosynthesis of sialylated glycans and are highly upregulated, up to 40-60%, in a range of cancers, with tumour hypersialylation strongly correlated with both tumour progression and treatment resistance. Accordingly, inhibiting sialylation is currently being explored by several research groups worldwide as a potential new cancer treatment strategy. However, to progress small molecule ST inhibitors into the clinic, issues around selectivity, synthetic accessibility, and cell permeability need to be addressed. Using computationally guided design principles, we produced a leading series of ST inhibitors by replacing the cytidine nucleoside with uridine and substituting the charged phosphodiester linker with a carbamate or triazole moiety. Biological evaluation of the newly developed inhibitors was performed using commercially available human ST enzymes, with the Ki inhibition values of the lead compounds ranging from 1 to 20 µM. Compared with earlier generations of sialylation inhibitors, our inhibitors are non-toxic in a range of cell studies, with improved synthetic accessibility.