2. Academic Validation
  3. 2-Azetidinones: Synthesis and biological evaluation as potential anti-breast cancer agents

2-Azetidinones: Synthesis and biological evaluation as potential anti-breast cancer agents

  • Eur J Med Chem. 2016 Nov 29:124:544-558. doi: 10.1016/j.ejmech.2016.08.041.
Ramasatyaveni Geesala 1,  Jagadeesh Kumar Gangasani 2,  Mahender Budde 3,  Sridhar Balasubramanian 4,  Jayathirtha Rao Vaidya 5,  Amitava Das 6
Affiliations

Affiliations

  • 1 Centre 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.
  • 2 Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India; National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500037, India.
  • 3 Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
  • 4 X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
  • 5 Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India; Academy of Scientific & Innovative Research, 2 Rafi Marg, New Delhi, 110 001, India; National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad, 500037, India.
  • 6 Centre 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. Electronic address: amitavadas@iict.res.in.
PMID: 27608432 DOI: 10.1016/j.ejmech.2016.08.041
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).

Keywords

2-Azetidinones; AKT kinase inhibition; Anti-proliferative effect; Apoptosis; Cell cycle arrest; Molecular docking.

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