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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Chem. | doi: 10.3389/fchem.2018.00456

DNA topoisomerase 1 structure-based design, synthesis, activity evaluation and molecular docking study of new 7-amide camptothecin derivatives against Spodoptera frugiperda

 Zhiyan Jiang1, 2, Zhijun Zhang1, 2, Gaofeng Cui1, 2, Zhipeng Sun1, 2, Gaopeng Song2, Yingqian Liu3* and  Guohua Zhong1, 2*
  • 1South China Agricultural University, China
  • 2South China Agricultural University, China
  • 3Lanzhou University, China

Camptothecin and its derivatives (CPTs) have strong toxicity to eukaryotic cells by targeting their DNA topoisomerase 1 (Top1) protein and have been increasingly explored as potential pesticides for plant protection. However, the detailed structure-binding mechanism of the interactions between CPTs and the insect Top1 protein remains unclear, which significantly hinders the development of novel CPTs as new insecticides. Herein, a series of 7-amide camptothecin analogues based on the binding mode of camptothecin in complex with Top1 (SfTop1)-DNA from Spodoptera frugiperda cultured cell line Sf9 were designed and synthesized. Fifteen of these compounds exhibited excellent cytotoxic activity (values of IC50 from 2.01 to 6.78 μM) compared with camptothecin (29.47 μM). The docking studies revealed the binding mechanism when the camptothecin parent rings were inserting parallel to DNA bases and stabling the ternary complex by π–π stacked and hydrogen-bond interactions, and further suggested that introduction of lipophilic and some electron-withdrawing groups on the amide linkage of camptothecin could be beneficial to its activity via some non-covalent interactions. Furthermore, almost all the synthesized compounds could inhibit the growth of Spodoptera litura larvae strongly (Inhibition rate from 50.20% to 79.05%), superior or comparable to camptothecin (55.69%) after 8 days of exposure. In particular, the compounds 4c, 4d, 4f, and 4j, which presented more than 70% inhibitory activities, were deserved to be developed as potential biorational pesticides. The information described here would be useful for the further design and development of potentially effective pesticides in the field of plant protection.

Keywords: Camptothecin, Synthesis, Topoisomerase 1, Binding mode, molecular docking, activity

Received: 15 Apr 2018; Accepted: 13 Sep 2018.

Edited by:

Simone Brogi, Università degli Studi di Siena, Italy

Reviewed by:

José Pedro Cerón-Carrasco, Universidad Católica San Antonio de Murcia, Spain
Judith A. Smith, University of Texas Health Science Center at Houston, United States  

Copyright: © 2018 Jiang, Zhang, Cui, Sun, Song, Liu and Zhong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Yingqian Liu, Lanzhou University, Lanzhou, China, yqliu@lzu.edu.cn
Prof. Guohua Zhong, South China Agricultural University, Guangzhou, China, guohuazhong@scau.edu.cn