Design, synthesis, and antitumor evaluation of morpholine substituted bisnaphthalimides as DNA targeting agents

Bioorg Med Chem Lett. 2023 Apr 1:85:129218. doi: 10.1016/j.bmcl.2023.129218.

Xiao-Man Chen ¹, Jian-Yu Zhou ¹, Shuang-Qiang Liu ¹, Long-Hao Song ¹, Hui-Ling Wang ¹, Qi Wang ¹, Si-Min Liang ¹, Lin Lu ¹, Jian-Hua Wei ², Rizhen Huang ³, Ye Zhang ⁴

Affiliations

1 Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 5411199, China.
2 Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 5411199, China. Electronic address: 352142863@qq.com.
3 Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 5411199, China. Electronic address: rzhuang1783@163.com.
4 Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 5411199, China. Electronic address: zhangye81@126.com.

PMID: 36894107 DOI: 10.1016/j.bmcl.2023.129218

Abstract

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro Anticancer activities against four Cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC₅₀ lowered to 0.09 μM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced Apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent Anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.

Keywords

Action mechanism; Anticancer agents; Bis-naphthalimides; DNA targeting; Topo I inhibition.

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