Design, synthesis and biological research of novel N-phenylbenzamide-4-methylamine acridine derivatives as potential topoisomerase I/II and apoptosis-inducing agents

Bioorg Med Chem Lett. 2019 Dec 1;29(23):126714. doi: 10.1016/j.bmcl.2019.126714.

Bin Zhang ¹, Zhende Dou ², Zheng Xiong ², Ning Wang ³, Shan He ², Xiaojun Yan ², Haixiao Jin ⁴

Affiliations

1 Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315800, People's Republic of China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, People's Republic of China.
2 Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315800, People's Republic of China.
3 Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, People's Republic of China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, People's Republic of China. Electronic address: wangning2@nbu.edu.cn.
4 Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315800, People's Republic of China. Electronic address: jinhaixiao@nbu.edu.cn.

PMID: 31635931 DOI: 10.1016/j.bmcl.2019.126714

Abstract

A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA Topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different Cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC₅₀ value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC₅₀ values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell Apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell Apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives.

Keywords

Acridine derivatives; Anticancer; DNA damage; Molecular docking; Topoisomerase I/II.

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