Novel lithocholic acid-diindolylmethane hybrids as potent sialyltransferase inhibitors targeting triple-negative breast cancer: a molecular hybridization approach

Molecular hybridization, an emerging strategy for the discovery of new anticancer therapeutics, shows promise as a powerful tool for the development of new sialyltransferase (ST) inhibitors for cancer treatment. This concept inspired the design of novel ST inhibitors through the hybridization of lithocholic acid and diindolylmethane, leading to the discovery of LCA-DIM hybrids as potential chemical entities targeting STs. Preliminary screening revealed the significance of the DIM moiety and incorporation of Asp linker on enhancing the inhibitory activity and selectivity of the hybrids towards ST6GAL1, inhibiting up to 100% of ST6GAL1 activity at 25 μM with no ST3GAL1 inhibition even at 500 μM. Incorporation of various 5,5'-substituents enhanced the inherent antimigration properties of the hybrids, with <b>IAN-5B</b> (R = Cl) and <b>IAN-15B</b> (R = N₃) presenting the highest antimigration activity across several triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, BT549, Hs578T) and considerable antiangiogenetic effect by suppressing HUVEC tube formation. This could be attributed to the excellent ST6GAL1 inhibitory activities of the two hybrids with IC₅₀ values of 6.6 ± 0.2 μM and 3.3 ± 0.1 μM, respectively. Overall, this study highlights LCA-DIM hybrids as novel, potent, and <i>N</i>-glycan-selective ST inhibitors with promising antimigration properties against aggressive TNBC.