Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 144, Issue -, Pages 595-611Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.12.050
Keywords
Triazole; Topo-II inhibition; Anticancer activity; Cell cycle; Apoptosis
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Funding
- UGC, New Delhi
- CSIR, New Delhi under the 12th Five Year Plan project Affordable Cancer Therapeutics (ACT) [CSC0301]
- Department of Science and Technology (DST), Government of India
- Centre Franco-Indien pour la Promotion de la Recherche Avancee (CEFIPRA)
- CSIR, New Delhi under the 12th Five Year Plan project ORIGIN [CSC-108]
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Topoisomerases (topo-I and topo-II) have occupied a significant role in DNA replication, transcription, and are a promising set of antitumor targets. In the present approach, a series of new 4 beta-amidotriazole linked podophyllotoxin derivatives (10a-i and 11a-k) were designed, synthesized by employing the click chemistry and their biological activities were evaluated. The majority of derivatives showed promising antiproliferative activity with IC50 values ranging from 1 to 10 mu M on the six human cancer cell lines; cervical (HeLa), breast (MCF-7), prostate (DU-145), lung (A549), liver (HepG2) and colon (HT-29). Among them, some of the congeners 10b, 10g and 10i have shown remarkable cytotoxicity with IC50 values of, < 1 mu M against the tested cancer cell lines and found to be more active than etoposide. Topoisomerase-mediated DNA relaxation assay results showed that the derivatives could efficiently inhibit the activity of topoisomerase-II. In addition, flow cytometry analysis on DU-145 cells revealed that these compounds arrest G2/M phase of cell cycle. Further apoptotic studies were also performed on these DU-145 cells, which showed that this class of compounds could induce apoptosis effectively. (C) 2017 Elsevier Masson SAS. All rights reserved.
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