Optimizing ST6GAL1 inhibition and selectivity using lithocholic acid-amino acid conjugates for antimetastatic and...

A series of LCA-aromatic amino acid conjugates were synthesized and tested for their inhibitory effects on N-glycan specific ST6GAL1 and O-glycan specific ST3GAL1. The LCA-amino acid conjugates with phenyl and indole moieties showed enhanced inhibitory activity and selectivity towards the N-glycan-specific ST6GAL1, with the indole-containing compound 4e exhibiting the highest activity (IC₅₀ = 20.0 ± 0.5 μM). In addition, compound 4e exhibited the highest antimetastatic potential, effectively inhibiting MDA-MB-231 cell migration at non-cytotoxic concentrations. Compound 4e also suppressed tumor growth and metastasis in vivo, attributing to its potential to disrupt integrins sialylation. The conjugate has also demonstrated excellent antiangiogenetic properties in vitro and ex vivo, owing to its ability to downregulate the VEGF/VEGFR2/Akt pathway. Taken together, these findings prove the practicality of employing LCA as a scaffold and aromatic amino acid conjugation in the discovery of novel, potent, and selective ST inhibitors necessary to address abnormal cell surface α-2,6-N-sialylation.