Cheng Yao, Yu Tsz Tin, Olzomer Ellen M, Hoehn Kyle L, Byrne Frances L, Kumar Naresh, Black David StC
School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Molecules. 2025 Apr 27;30(9):1938. doi: 10.3390/molecules30091938.
The Warburg effect, a unique glycolytic phenomenon in cancer cells, presents a promising target for developing selective anticancer agents. Previously, , 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 -derived salt compounds was synthesized. Among these, exhibited nanomolar anticancer activity (IC = 22.97 nM) and a high selectivity ratio (IC of non-cancerous cells/IC of cancer cells = 41.43). Molecular docking revealed that all naphthoimidazole salt analogues (-) bind to Keap1 via carbonyl-mediated interactions, with variations in hydrogen-bonding residues (e.g., VAL606, ILE559).
瓦伯格效应是癌细胞中一种独特的糖酵解现象，是开发选择性抗癌药物的一个有前景的靶点。此前，通过表型筛选鉴定出一种破坏糖酵解代谢的先导化合物，并提出 Kelch 样 ECH 相关蛋白 1（Keap1）作为潜在靶点。为了提高其效力和选择性，合成了一系列该先导化合物衍生的盐类化合物。其中，该化合物表现出纳摩尔级的抗癌活性（IC = 22.97 nM）和高选择性比（非癌细胞的 IC/癌细胞的 IC = 41.43）。分子对接显示，所有萘并咪唑盐类似物（-）通过羰基介导的相互作用与 Keap1 结合，氢键残基存在差异（例如 VAL606、ILE559）。
