Triazolo-thiadiazepine as a potent apoptotic DNA degradation agent and MetAP2 inhibitor against human breast adenocarcinoma cells

Sunil, Dhanya and Isloor, Arun M and Shetty, Prakash and Pai, KSR and Balaji, S (2015) Triazolo-thiadiazepine as a potent apoptotic DNA degradation agent and MetAP2 inhibitor against human breast adenocarcinoma cells. Chemistry and Biology Interface, 5 (1). pp. 63-75. ISSN 2249 –4820

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Breast cancer is the second leading cause of cancer deaths in females. In the present research work, two new chalcones, (2E)-1-(4-fluorophenyl)-3-[3-substituted)-1H-pyrazol-4-yl]prop-2-en-1-ones have been synthesized by Claisen-Schmidt reaction between pyrazole carbaldehydes and 4-fluoroacetophenone. A novel series of 3-[(substituted)methyl]-6-(4-fluorophenyl)-8-(3-substituted-1H-pyrazol-4-yl)-5,8- dihydro[1,2,4]triazolo[3,4-b][1,3,4] thiadiazepines were prepared by the base catalysed reaction between chalcones and 5-substituted-4-amino-3-mercapto-1,2,4-triazoles and were characterized by elemental analysis and spectroscopic techniques. 3-[(2-methylphenoxy)methyl]-6-(4-fluorophenyl)-8-(3-(4-fluorophenyl)- 1H-pyrazol-4-yl)-5,8-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine (4e), displayed excellent cytotoxic activity in MCF-7 cells with very low IC50 of 5 μg/mL compared to the standard drug Doxorubicin, in the MTT assay. 4e at 10 μg/mL exhibited a highly significant concentration dependent increase in tail length and olive tail moment leading to apoptotic DNA degradation in comet assay. MetAP2, a bifunctional enzyme involved in angiogenesisis, found overexpressed in cancer cells and essential for the progression of solid tumors was used as the target for molecular docking studies to investigate the inhibitory action of 4e. The favourable binding interactions as 4e positions itself into the active site of MetAP2 and its compliance with Ro5 suggests it to be a potent chemotherapeutic agent in the treatment of breast adenocarcinoma. Chalcones revealed better antioxidant properties in in-vitro DPPH and ABTS scavenging assays than thiadiazepines.

Item Type: Article
Uncontrolled Keywords: Thiadiazepine, cytotoxicity, apoptosis, MetAP2, antioxidant.
Subjects: Engineering > MIT Manipal > Biotechnology
Engineering > MIT Manipal > Chemistry
Pharmacy > MCOPS Manipal > Pharmacology
Engineering > MIT Manipal > Printing and Media
Depositing User: MIT Library
Date Deposited: 30 Apr 2015 07:04
Last Modified: 30 Apr 2015 07:04

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