Design, synthesis, topoisomerase I & II inhibitory activity, antiproliferative activity, and structure–activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase IIα catalytic inhibitor. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Ahmad, Pervez; Woo, Hyunjung; Jun, Kyu-Yeon; Kadi, Adnan A.; Abdel-Aziz, Hatem A.; Kwon, Youngjoo; Rahman, A.F.M. Motiur
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 8(2016)
• Page Start: 1898
• Page End: 1908
• Publication Date: 2016-04-15
• Subjects: Pyrazoline derivatives -- Antiproliferative activity -- Topoisomerase -- ATP-competitive inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.03.017
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Synthesis a series of pyrazoline derivatives. ATP-competitive human topoisomerase IIα catalytic inhibitor. Inhibited endogenous topo-mediated pBR322 plasmid relaxation more efficiently than Etoposide. Abstract: A series of pyrazoline derivatives (5 ) were synthesized in 92–96% yields from chalcones (3 ) and hydrazides (4 ). Subsequently, topo-I and IIα-mediated relaxation and antiproliferative activity assays were evaluated for5 . Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100 μM. Nevertheless, all the compounds5a –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 μM (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1 μM). Moreover, compounds5c, 5f and5i were observed to have strong antiproliferative activity against BT474 cell lines. Since, compound5d showed antiproliferative activity at a very low IC50 thus5d was then selected to study on their mode of action with diverse methods of ATP competition assay, ATPase assay and DNA-topo IIα cleavable complex assay and the results revealed that it functioned as a ATP-competitive human topoisomerase IIα 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 μM) than Etoposide (36.0 ± 1.7% at 50 μM).