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Are the Cytotoxic Properties of Conjugated Unsaturated Ketones Inactivated by Thiols?

A Doroudi1, P K Roayapalley2, S Das3

  • 1Drug Discovery and Development Research Cluster ; University of Saskatchewan, Saskatoon, Canada, School of Pharmacy.

Die Pharmazie
|August 4, 2023
PubMed

Insights

Converting cytotoxic enones into thiol adducts maintains or enhances their potency against colon cancer cells. These compounds show selective toxicity towards cancer cells and favorable ADME properties.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Conjugated unsaturated ketones (enones) are cytotoxic compounds.
  • Understanding structure-activity relationships is crucial for developing new cancer therapeutics.

Purpose of the Study:

  • To investigate if converting enones to thiol adducts affects their cytotoxic potency.
  • To evaluate the efficacy and selectivity of enones and their thiol adducts against colon cancer.

Main Methods:

  • Synthesis and evaluation of various enones and their thiol adducts.
  • Cytotoxicity assays using human HCT116 and HT29 colon cancer cell lines.
  • Comparison of toxicity against non-malignant CRL1790 cells to determine selectivity.

Main Results:

  • Many compounds exhibited IC50 values below 10 μM, with some exceeding the toxicity of 5-FU.
  • Thiol adducts were equipotent or more potent than their parent enones.
  • Significant selective toxicity was observed against HCT116 and HT29 neoplasms compared to CRL1790 cells, yielding high Selectivity Index values.
  • Compounds demonstrated favorable Absorption, Distribution, Metabolism, and Excretion (ADME) properties.

Conclusions:

  • Conversion to thiol adducts does not diminish, and can enhance, the cytotoxic potency of enones.
  • These novel compounds represent promising candidates for colon cancer therapy due to their potent and selective cytotoxicity.
  • Favorable ADME profiles suggest potential for clinical development.

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