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Synthesis and Evaluation of Fuligocandin B Derivatives with Activity for Overcoming TRAIL Resistance

Midori A Arai1, Ayaka Masuda1, Akiko Suganami2

  • 1Graduate School of Pharmaceutical Sciences, Chiba University.

Chemical & Pharmaceutical Bulletin
|August 3, 2018
PubMed

Insights

Researchers synthesized novel compounds to overcome cancer cell resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy. A quinoline derivative and a modified fuligocandin B derivative showed significant potential in sensitizing resistant cancer cells to TRAIL-induced apoptosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway triggers apoptosis in cancer cells, offering therapeutic potential.
  • TRAIL resistance in cancer cells is a significant clinical challenge, necessitating strategies to enhance TRAIL sensitivity.
  • Small molecules that can overcome TRAIL resistance are crucial for developing effective cancer treatments.

Purpose of the Study:

  • To synthesize and evaluate novel heterocyclic derivatives of fuligocandin B for their ability to overcome TRAIL resistance in cancer cells.
  • To identify potent compounds that can sensitize TRAIL-resistant cancer cells to apoptosis induction.
  • To explore structure-activity relationships and design improved TRAIL sensitizers.

Main Methods:

  • Synthesis of heterocyclic derivatives based on the natural product fuligocandin B.
  • Evaluation of synthesized compounds for their activity in sensitizing TRAIL-resistant cancer cells.
  • In silico molecular docking studies to identify potential target proteins, such as valosin-containing protein.
  • Design and synthesis of new derivatives based on docking study insights.

Main Results:

  • Several synthesized heterocyclic derivatives demonstrated activity in overcoming TRAIL resistance.
  • A specific quinoline derivative (10g) exhibited potent activity against TRAIL-resistant gastric adenocarcinoma cells.
  • Compound 10m (7'-amino fuligocandin B), designed after docking studies, showed significant TRAIL-sensitizing activity.
  • Compound 10m demonstrated superior efficacy compared to the parent compound fuligocandin B in sensitizing cells to TRAIL.

Conclusions:

  • Novel fuligocandin B derivatives, particularly quinoline and 7'-amino derivatives, are effective in overcoming TRAIL resistance in cancer cells.
  • These compounds hold promise as potential therapeutic agents to enhance the efficacy of TRAIL-based cancer treatments.
  • Further investigation into the mechanism of action and in vivo efficacy of these compounds is warranted.
Keywords:
cancercytotoxicityinhibitornatural producttumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

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