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2-Azetidinones: Synthesis and biological evaluation as potential anti-breast cancer agents
Ramasatyaveni Geesala1, Jagadeesh Kumar Gangasani2, Mahender Budde3
1Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India; Academy of Scientific & Innovative Research, 2 Rafi Marg, New Delhi, 110 001, India.
Abstract:
A series of twenty-five 2-azitidinone (β-lactam) derivatives were synthesized and evaluated for anti-cancer properties against breast cancer, MCF-7 and MDA-MB-231. These β-lactam derivatives depicted significant cytotoxicity in cancer cell lines but not in normal human mammary epithelial cells, MEpiC. Interestingly, derivatives of 2-bromo ethyl acrylonitrile (19w) exhibited - potent anti-proliferative activity with IC50, 5.79 ± 0.01 μM in MCF-7 and 6.86 ± 0.009 μM in MDA-MB-231. In addition, an increased expression of pro-apoptotic genes (p53, Bax, Bid) as well as decreased mRNA expression of cyclins D1, E and Cdk 2, 6 along with cell cycle arrest at G1 phase was observed. 19w treatment has shown higher percentage of Annexin-positive cells indicating induction of apoptosis. Further, docking studies confirmed an interaction between 19w and ATP-binding catalytic site of AKT1. Mechanistically, 19w depicted dose-dependent decrease in phosphorylation of AKT and GSK-3β and significant decrease in AKT kinase activity. In conclusion, β-lactam derivative 19w is a potential anti-breast cancer therapeutic candidate targeting cell survival pathway (AKT/GSK3β).
Insights
Novel β-lactam derivative 19w shows potent anti-cancer activity against breast cancer cells. This compound selectively targets the AKT/GSK3β pathway, offering a promising therapeutic candidate for breast cancer treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- Breast cancer remains a leading cause of cancer-related deaths globally, necessitating the development of novel therapeutic agents.
- Existing treatments often face challenges with resistance and side effects, highlighting the need for new drug candidates with improved efficacy and selectivity.
- The β-lactam scaffold has shown potential in various biological activities, including anticancer effects, making it an attractive starting point for drug discovery.
Purpose of the Study:
- To synthesize and evaluate novel 2-azitidinone (β-lactam) derivatives for their anticancer properties against human breast cancer cell lines (MCF-7 and MDA-MB-231).
- To investigate the mechanism of action of the most potent derivative, focusing on its effects on apoptosis, cell cycle progression, and key signaling pathways.
- To assess the selectivity of the synthesized compounds against cancer cells versus normal human mammary epithelial cells (MEpiC).
Main Methods:
- Synthesis of twenty-five β-lactam derivatives and their in vitro evaluation for cytotoxicity against MCF-7, MDA-MB-231, and MEpiC cell lines.
- Analysis of gene expression changes (p53, Bax, Bid, cyclins D1, E, Cdk 2, 6) and cell cycle distribution (G1 phase arrest) following treatment with the lead compound.
- Apoptosis induction was assessed by Annexin V staining, and molecular mechanisms were explored using docking studies, Western blotting (p-AKT, p-GSK-3β), and kinase activity assays.
Main Results:
- Several β-lactam derivatives exhibited significant cytotoxicity against breast cancer cell lines, with minimal impact on normal MEpiC cells.
- The derivative 2-bromo ethyl acrylonitrile (19w) demonstrated potent anti-proliferative activity with IC50 values of 5.79 ± 0.01 μM (MCF-7) and 6.86 ± 0.009 μM (MDA-MB-231).
- Compound 19w induced apoptosis, caused G1 cell cycle arrest, modulated pro-apoptotic and cell cycle regulatory gene expression, and inhibited the AKT/GSK-3β signaling pathway by reducing AKT and GSK-3β phosphorylation and AKT kinase activity.
Conclusions:
- The β-lactam derivative 19w is a highly promising candidate for anti-breast cancer therapy.
- Compound 19w exhibits potent and selective anticancer effects through the induction of apoptosis and cell cycle arrest.
- The mechanism of action involves the targeted inhibition of the AKT/GSK-3β cell survival pathway, suggesting its potential as a novel therapeutic strategy for breast cancer.
