Anticancer potential of novel α,β-unsaturated γ-lactam derivatives targeting the PI3K/AKT signaling pathway

Biochem Pharmacol. 2021 Aug:190:114659. doi: 10.1016/j.bcp.2021.114659. Epub 2021 Jun 17.


Six recently synthesized alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates were evaluated for their potential as cytotoxic and anticancer agents. All compounds were tested in the ERα positive MCF-7, triple negative MDA-MB-231, and Her2+ SKBR-3 breast cancer cell lines. The most lipophilic derivatives, bearing the 4-isopropylphenyl (2) or 4-tert-butylphenyl (3) group at the γ-lactam nitrogen, proved to be cytotoxic against all the cancer cell lines tested (IC50 values ranging from 18 to 63 μM), exerting their greatest activity in SKBR-3 cells, with IC50 values of 33 and 18 μM, respectively. Biological studies showed that the cytotoxic effects of 2 and 3 are accompanied by apoptotic death in breast cancer cells, and both compounds showed no significant toxicity on healthy cells (e.g., MCF-10A) and red blood cells. An in-depth mechanistic study based on molecular biology, immunoblotting analysis and in silico docking calculations suggested that α,β-unsaturated γ-lactam derivatives could interfere with the functioning of PI3K and PDK-1, two key enzymes in the PI3K/AKT signaling pathway, whose overactivation is related to the regulation of cell growth and survival in several malignancies.

Keywords: Apoptosis; Breast cancer; Cytotoxicity; PI3K/AKT signaling pathway; α,β-Unsaturated lactams; α-Methylene-γ-lactams.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Biological Products
  • Breast Neoplasms / drug therapy*
  • Cell Cycle / drug effects
  • Cell Survival / drug effects
  • Epithelial Cells / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*


  • Antineoplastic Agents
  • Biological Products
  • Lactams
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt