Structure-activity relationship studies on O-alkylamino-tethered salicylamide derivatives with various amino acid linkers as potent anticancer agents.

In our continued SAR study efforts, a series of O-alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast cancer (BC) and triple-negative breast cancer (TNBC) cell lines with low micromolar IC50 values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC50 = 3.38 ± 0.37 μM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC50 > 60 μM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising anticancer drug candidate for further clinical development.