Synthesis of novel pyrazole derivatives as promising DNA-binding agents and evaluation of antitumor and antitopoisomerase I/II activities

• Published in: Chemical & pharmaceutical bulletin p. c18-00546
• Main Authors: Feng, Jiajia, Qi, Hui, Sun, Xiaoyang, Feng, Siran, Liu, Zhenming, Song, Yali, Qiao, Xiaoqiang
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2018
• Subjects: Antitopoisomerase; Antitumor; DNA; pyrazole; pyrazole; Antitopoisomerase; DNA; Antitumor
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c18-00546

Molecules bearing pyrazole nucleus present diverse biological properties such as antitumor and anti-inflammatory activities that can be associated with DNA interactions. This study aimed to the synthesis of new pyrazol derivatives and evaluated their ability to interact with the DNA and antitumor and topoisomerase inhibition activities. All derivatives were successfully synthesized, and their structures were elucidated by 1HNMR and HRMS (ESI+). Antiproliferative inhibition assays, UV titration assays, fluorescence titration assays, circular dichroism (CD) assays, KI quenching studies, topoisomerase inhibitory activity assays and molecular docking were evaluated for these compounds. Especially, compounds 5e and 5q showed higher antitumor activity with IC50 values <13 μM for the tested cell lines. However, compounds 5e and 5q did not inhibit the topoisomerase activity evaluated by relaxation assay. These results show that the pyrazole nucleus contributes to the incorporation of molecules into the DNA. Moreover, it was highlighted that positive charges are relevant for the design of promising antitumor and DNA binding compounds.