Based on reported pharmacophores as topoisomerase inhibitors, 2,5-dimethylthiophene/furan based N-acetyl pyrazolines were designed and envisaged as topoisomerase inhibitors. The target compounds were synthesized and tested in vitro against human topoisomerases in decatenation, relaxation, cleavage complex and DNA intercalation assays. Out of 29 compounds, three (10, 11 and 29) showed potent and selective topoisomerase II inhibitory activity with no intercalation with DNA. Further, molecular docking studies also endorsed them as ATP dependent topoisomerase II catalytic inhibitors. These compounds exerted potential anticancer effects on breast, colon, lung and prostate cancer cell lines at a low micromolar level, as compared to etoposide, and low toxicity to normal cells. Apart from the topoisomerase II inhibition, these compounds also induced a reactive oxygen species (ROS) level in cancer cells. The cell cycle analyses showed their apoptotic effect at the G1 phase.
Synthesis and biological evaluation of new 2,5-dimethylthiophene/furan based N-acetyl pyrazolines as selective topoisomerase II inhibitors
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Corresponding authors
a
Laboratory for Drug Design and Synthesis, Centre for Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, India
E-mail: raj.khunger@gmail.com, rajcps@cup.ac.in
Fax: +91-1636-236564
Tel: +91-0164-2864215
E-mail: raj.khunger@gmail.com, rajcps@cup.ac.in
Fax: +91-1636-236564
Tel: +91-0164-2864215
b
Indo-Soviet Friendship College of Pharmacy, Moga, India
c
Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Mohali, S. A. S. Nagar, Sec 67, India
d
Centre for Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
RSC Adv., 2016,6, 14880-14892
DOI: 10.1039/C5RA25705K
Scheme 1 Reagents and conditions: (a) 5% NaOH, ethanol, rt, 4–5 h, 65–82% (b) NH2NH2·H2O, CH3COOH, reflux, 4–6 h, 75–90%.
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