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  2. Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors

Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors

  • Bioorg Chem. 2022 Feb;119:105543. doi: 10.1016/j.bioorg.2021.105543.
Zhi-Ying Li 1 Guang-Sen Xu 1 Yu-Liang Song 1 Xun Li 2
Affiliations

Affiliations

  • 1 Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, China.
  • 2 Institute of Materia Medica, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, Shandong 250117, China; Key Laboratory of Forensic Toxicology, Ministry of Public Security, Beijing 100192, China. Electronic address: lixun@sdfmu.edu.cn.
Abstract

Previously, an array of N-substituted acridone derivatives have been reported as potent Topoisomerase II (Topo II) inhibitors, and preliminary structure-activity relationship (SAR) outcomes revealed that the linker between 1-NH and N-methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived Topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N-methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed Topo II Inhibitor 6 h was found to be more potent than E17 and E24, thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/β inhibitor, caused obvious DNA damage, and induced Apoptosis by triggering the loss of mitochondrial membrane potential (Δψm). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIβ subtypes.

Keywords

N-substituted acridone derivatives; Structural optimization; Structure-activity relationship; Topo IIα/β inhibitor.

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