Development and synthesis of diffractaic acid analogs as potent inhibitors of colorectal cancer stem cell traits

Sci Rep. 2025 Feb 25;15(1):6695. doi: 10.1038/s41598-025-90552-9.

Abstract

In recent years, evidence for the anti-cancer activity of lichen secondary metabolites has been rapidly increasing. In this study, we synthesised analogues of diffractaic acid, a lichen secondary metabolite, and evaluated their ability to suppress colorectal cancer stem potential. Among the 10 compounds after H/CH₃/benzylation of the diffractaic acid structure or modifications in an aromatic hydrophobic domain, TU3 has a more inhibition effect on the stem potential of colorectal cancer compared to other compounds. The compound TU3 targets ALDH1 and suppresses key signalling pathways such as WNT, STAT3, NF-κB, Hedgehog, and AP-1. Inhibition of these signalling pathways by TU3 contribute to attenuate the survival mechanisms of colorectal cancer stem cell and thus inhibit cancer progression.

Keywords: ALDH1; Colorectal cancer stem cells; Diffractaic acid analogs; Lichen secondary metabolites; Structure-based modifications.

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Humans
  • Neoplastic Stem Cells* / drug effects
  • Neoplastic Stem Cells* / metabolism
  • Neoplastic Stem Cells* / pathology
  • Retinal Dehydrogenase / antagonists & inhibitors
  • Retinal Dehydrogenase / metabolism
  • Signal Transduction / drug effects

Substances

  • Aldehyde Dehydrogenase 1 Family
  • Antineoplastic Agents
  • Retinal Dehydrogenase
  • ALDH1A1 protein, human