Modulating polybasic character of galactose-based glycosylated antitumor ether lipids for enhanced cytotoxic response

We describe the structure-activity relationship studies of galactose-based glycosylated antitumor ether lipids (GAELs) by installing amine groups at different positions of galactose and the glycerol backbone. Different dibasic and tribasic analogues of <i>galacto</i>-GAELs were synthesized and tested against a panel of human epithelial cancer cell lines. A β-anomeric triamino galactose scaffold, was the most active compound of the series and displayed CC₅₀ in the range of 2.6 ± 0.2 μM to 6.5 ± 0.1 μM against various epithelial cancer cell lines. This compound exhibited superior activity to kill cancer cells than cisplatin. The hit GAEL compound did not induce caspase activation and therefore, the cell-killing effect does not occur due to caspase-mediated apoptosis. This observation is in line with the previously reported GAEL prototypes.