Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents

  • Bioorg Chem. 2024 Jul 25:151:107665. doi: 10.1016/j.bioorg.2024.107665.
Yao Cheng  1 ,  John Patrick Jones  1 ,  Tsz Tin Yu  1 ,  Ellen M Olzomer  2 ,  Jacky Su  1 ,  Alice Katen  1 ,  David StC Black  1 ,  Gene Hart-Smith  3 ,  Elizabeth S Childress  4 ,  Marc R Wilkins  2 ,  Isabel A Mateos  2 ,  Webster L Santos  4 ,  Kyle L Hoehn  2 ,  Frances L Byrne  5 ,  Naresh Kumar  6
Affiliations
  • 1. School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
  • 2. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
  • 3. Australian Proteome Analysis Facility, Macquarie University, Macquarie Park, NSW 2109, Australia.
  • 4. Department of Chemistry and VT Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
  • 5. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: [email protected].
  • 6. School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: [email protected].
PMID: 39094508 DOI: 10.1016/j.bioorg.2024.107665
Abstract

Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting Cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A Cancer cells with an IC50 of 2.60 μM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.

Keywords
Anticancer; Glycolysis; Naphthoimidazole; Pharmacokinetic; Pull-down assay.
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