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, <b>BH10</b>, 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 <b>BH10</b>-derived salt compounds was synthesized. Among these, <b>7b</b> exhibited nanomolar anticancer activity (IC<sub>50</sub> = 22.97 nM) and a high selectivity ratio (IC<sub>50</sub> of non-cancerous cells/IC<sub>50</sub> of cancer cells = 41.43). Molecular docking revealed that all naphthoimidazole salt analogues (<b>7a</b>-<b>f</b>) bind to Keap1 via carbonyl-mediated interactions, with variations in hydrogen-bonding residues (e.g., VAL606, ILE559).
Authors
- Kyle L. Hoehn (ORCID: https://orcid.org/0000-0002-0214-3238)
- Yao Cheng
- Frances L. Byrne (ORCID: https://orcid.org/0000-0002-8897-8438)
- David StC. Black (ORCID: https://orcid.org/0000-0001-9300-4737)
- Tsz Tin Yu (ORCID: https://orcid.org/0000-0002-8484-7342)
- Ellen M. Olzomer (ORCID: https://orcid.org/0000-0002-5823-0736)
- Naresh Kumar (ORCID: https://orcid.org/0000-0002-0951-9621)
Institutions
- UNSW Sydney (AU)
Publication Details
- Journal
- Molecules
- Published
- 2025-04-27
- DOI
- https://doi.org/10.3390/molecules30091938
- Citations
- 3
- Primary Topic
- Bioactive Compounds and Antitumor Agents
- Type
- article
- Field-Weighted Citation Impact
- 3.92
Funders
- Cancer Institute NSW