2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2016 Apr 15;24(8):1898-908. doi: 10.1016/j.bmc.2016.03.017.
Pervez Ahmad 1,  Hyunjung Woo 2,  Kyu-Yeon Jun 2,  Adnan A Kadi 1,  Hatem A Abdel-Aziz 3,  Youngjoo Kwon 4,  A F M Motiur Rahman 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 2 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea.
  • 3 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt.
  • 4 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
  • 5 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: afmrahman@ksu.edu.sa.
PMID: 26988802 DOI: 10.1016/j.bmc.2016.03.017
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 for 5. Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100 μM. 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 μM (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1 μM). 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 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).

Keywords

ATP-competitive inhibitor; Antiproliferative activity; Pyrazoline derivatives; Topoisomerase.

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