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Synthesis and biological evaluation of disulfides as anticancer agents with thioredoxin inhibition

Xiangxu Wei1, Miao Zhong1, Song Wang1

  • 1State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.

Bioorganic Chemistry
|March 23, 2021
PubMed

Insights

Researchers developed a new method to screen for thioredoxin (Trx) inhibitors and identified compound 68. This compound shows potent anticancer activity by inducing apoptosis in cancer cells through Trx inhibition.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Medicinal Chemistry

Background:

  • Cancer cells exhibit altered redox homeostasis, making thioredoxin (Trx) a potential drug target.
  • Trx is crucial for maintaining intracellular redox balance and is implicated in cancer cell growth and survival.

Purpose of the Study:

  • To synthesize and evaluate disulfides as Trx inhibitors and anticancer agents.
  • To establish an efficient screening method for Trx inhibitors.

Main Methods:

  • Synthesis of 72 disulfide compounds.
  • Screening of Trx inhibitory activity using the NBL-SS probe in living cells.
  • Evaluation of cytotoxicity against HeLa and normal cell lines.
  • Kinetic studies and mechanistic investigation of lead compounds.

Main Results:

  • An efficient screening method for Trx inhibitors was established.
  • Eight disulfides demonstrated significant Trx inhibition.
  • Compounds 68 and 69 showed high cytotoxicity to HeLa cells with minimal impact on normal cells.
  • Compound 68 exhibited faster Trx inhibition kinetics and induced apoptosis in HeLa cells via reactive oxygen species accumulation.

Conclusions:

  • The developed screening method is effective for identifying Trx inhibitors.
  • Compound 68 is a promising anticancer candidate due to its potent Trx inhibition and selective cytotoxicity.
  • Targeting Trx represents a viable strategy for developing novel anticancer therapeutics.
Keywords:
AnticancerApoptosisDisulfideOxidative stressThioredoxin

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