Design, synthesis and biological evaluation of naphthalene-1,4-dione analogues as anticancer agents

The increased metabolism of glucose <i>via</i> aerobic glycolysis, known as the Warburg effect, is a hallmark of most cancers. Identifying molecules that disrupt the Warburg effect may allow for selective cytotoxicity towards cancer cells and reduce side effects compared to current chemotherapy agents. Our initial hit compound, BH10, which potentially targets Kelch-like ECH-associated protein 1 (Keap1), increased oxygen consumption rate and displayed increased cytotoxicity towards cancer cells over normal cells <i>in vitro</i>. In this project, a library of analogues based on the BH10 scaffold was prepared with the aim of improving potency and cancer-cell specificity. Among these analogues, several compounds showed notable potency, with activity (IC₅₀) observed around 1 μM. However, when considering selectivity, the imidazole derivative, compound 44, exhibited the most optimal balance, achieving an IC₅₀ of 6.4 μM and selectivity ratio of 3.6 which indicates greater toxicity to cancer cells <i>vs.</i> normal cells.