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Design, synthesis, topoisomerase I & II inhibitory activity, antiproliferative activity, and structure-activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase II alpha catalytic inhibitor
- Design, synthesis, topoisomerase I & II inhibitory activity, antiproliferative activity, and structure-activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase II alpha catalytic inhibitor
- Ahmad, Pervez; Woo, Hyunjung; Jun, Kyu-Yeon; Kadi, Adnan A.; Abdel-Aziz, Hatem A.; Kwon, Youngjoo; Rahman, A. F. M. Motiur
- Ewha Authors
- 권영주; 전규연
- SCOPUS Author ID
- Issue Date
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY
- 0968-0896; 1464-3391
- vol. 24, no. 8, pp. 1898 - 1908
- Pyrazoline derivatives; Antiproliferative activity; Topoisomerase; ATP-competitive inhibitor
- PERGAMON-ELSEVIER SCIENCE LTD
- SCI; SCIE; SCOPUS
- A series of pyrazoline derivatives (5) were synthesized in 92-96% yields from chalcones (3) and hydrazides (4). Subsequently, topo-I and II alpha-mediated relaxation and antiproliferative activity assays were evaluated for 5. Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100 mu M. Nevertheless, all the compounds 5a-5i showed significant topo II inhibitory activity in the range of 90-94% (Etoposide, 96%) at the same concentration. Cytotoxic potential of these compounds was tested in a panel of three human tumor cell lines, HCT15, BT474 and T47D. All the compounds showed strong activity against HCT15 cell line with IC50 at the range of 1.9-10.4 mu M (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1 mu M). Moreover, compounds 5c, 5f and 5i were observed to have strong antiproliferative activity against BT474 cell lines. Since, compound 5d showed antiproliferative activity at a very low IC50 thus 5d was then selected to study on their mode of action with diverse methods of ATP competition assay, ATPase assay and DNA-topo II alpha cleavable complex assay and the results revealed that it functioned as a ATP-competitive human topoisomerase II alpha catalytic inhibitor. Further evaluation of endogenous topo-mediated DNA relaxation in cells has been conducted to find that, 5d inhibited endogenous topo-mediated pBR322 plasmid relaxation is more efficient (78.0 +/- 4.7% at 50 mu M) than Etoposide (36.0 +/- 1.7% at 50 mu M). (C) 2016 Elsevier Ltd. All rights reserved.
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