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Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell

Ridong Li1, Xianling Ning2, Shuo Zhou3

  • 1Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, PR China; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China.

European Journal of Medicinal Chemistry
|November 25, 2017
PubMed

Insights

Researchers identified novel 4-hydroxy-thiazolidine-2-thione compounds that activate pyruvate kinase M2 (PKM2), a key protein in cancer metabolism. Compound 5w demonstrated potent anti-cancer effects and cell cycle arrest, offering a promising new therapeutic avenue.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Cancer Biology

Background:

  • Pyruvate kinase M2 (PKM2) plays a critical role in the aerobic glycolysis characteristic of cancer cells.
  • Modulating PKM2 activity presents a potential strategy for targeting aberrant cancer cell metabolism.

Purpose of the Study:

  • To discover novel activators of PKM2.
  • To design and synthesize 4-hydroxy-thiazolidine-2-thione derivatives as potent PKM2 activators.
  • To evaluate the anti-proliferative and pharmacological effects of these compounds on human cancer cell lines.

Main Methods:

  • Random screening of an in-house compound library to identify lead PKM2 activators.
  • Design and synthesis of novel 4-hydroxy-thiazolidine-2-thione derivatives.
  • In vitro anti-proliferative assays against various human cancer cell lines (H1299, HCT116, Hela, PC3) and a non-tumor cell line (HELF).
  • Cell cycle analysis using flow cytometry.
  • Molecular docking studies to rationalize PKM2 activation.

Main Results:

  • A novel 4-hydroxy-thiazolidine-2-thione compound (compound 2) was identified as a PKM2 activator.
  • Several synthesized derivatives exhibited enhanced PKM2 activation and potent anti-proliferative activity at nanomolar concentrations.
  • Compound 5w showed significant anti-proliferative effects (IC50: 0.46–0.81 μM) against multiple cancer cell lines with reduced cytotoxicity in normal cells.
  • Compound 5w induced G2/M phase cell cycle arrest in HCT116 cells.
  • Compound 5t demonstrated optimal PKM2 activation, supported by docking studies.

Conclusions:

  • Novel 4-hydroxy-thiazolidine-2-thione derivatives are effective PKM2 activators with significant anti-cancer properties.
  • Compound 5w is a promising candidate for further development as an anti-tumor agent due to its potent efficacy and selectivity.
  • The study provides a basis for developing PKM2-targeting cancer therapeutics.
Keywords:
4-Hydroxy-Thiazolidine-2-thione derivativesAnti-tumor activityPKM2 activatorsStructure-activity relationship

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