2-Azetidinones: Synthesis and biological evaluation as potential anti-breast cancer agents.
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 G1phase 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).
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.
Ramasatyaveni
R
Geesala
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.
Jagadeesh Kumar
JK
Gangasani
Division of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
Mahender
M
Budde
X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
Sridhar
S
Balasubramanian
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.
Jayathirtha Rao
JR
Vaidya
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.
Amitava
A
Das
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D015394:Molecular Structure
C116379:2-azetidinone; D000970:Antineoplastic Agents; D001384:Azetidines
2-Azetidinones; AKT kinase inhibition; Anti-proliferative effect; Apoptosis; Cell cycle arrest; Molecular docking