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

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Breast cancer comprises various subtypes with distinct therapeutic challenges.
• Targeting key signaling pathways like PI3K/AKT is crucial for developing effective anticancer therapies.

Purpose of the Study:

• To synthesize and evaluate novel alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates as potential cytotoxic and anticancer agents.
• To investigate the mechanism of action and safety profile of the most promising compounds.

Main Methods:

• Synthesis of six alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates.
• Cytotoxicity assays on ERα positive (MCF-7), triple negative (MDA-MB-231), and Her2+ (SKBR-3) breast cancer cell lines.
• Apoptosis assays, toxicity assessment on healthy cells (MCF-10A) and red blood cells.
• Mechanistic studies including molecular biology, immunoblotting, and in silico docking.

Main Results:

• Compounds 2 and 3, featuring lipophilic phenyl groups, exhibited significant cytotoxicity across all tested breast cancer cell lines (IC50: 18–63 μM).
• Compounds 2 and 3 demonstrated highest efficacy against SKBR-3 cells (IC50: 33 and 18 μM, respectively).
• Cytotoxic effects were linked to apoptosis induction, with no significant toxicity observed in healthy cells or red blood cells.

Conclusions:

• Alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates, particularly derivatives 2 and 3, represent promising candidates for breast cancer therapy.
• These compounds likely exert their effects by interfering with the PI3K/AKT signaling pathway, involving PI3K and PDK-1 inhibition.
• The observed safety profile suggests a favorable therapeutic window for these novel agents.