Design, Synthesis, and Biological Evaluation of Naphthoquinone Salts as Anticancer Agents.

The Warburg effect, a unique glycolytic phenomenon in cancer cells, presents a promising target for developing selective anticancer agents. Previously, BH10, a hit compound disrupting glycolytic metabolism, was identified via phenotypic screening, with Kelch-like ECH-associated protein 1 (Keap1) proposed as a potential target. To enhance its potency and selectivity, a library of BH10-derived salt compounds was synthesized. Among these, 7b exhibited nanomolar anticancer activity (IC(50) = 22.97 nM) and a high selectivity ratio (IC(50) of non-cancerous cells/IC(50) of cancer cells = 41.43). Molecular docking revealed that all naphthoimidazole salt analogues (7a-f) bind to Keap1 via carbonyl-mediated interactions, with variations in hydrogen-bonding residues (e.g., VAL606, ILE559).