2. Academic Validation
  3. Discovery of 4-(N-dithiobenzyl piperazine)-1,8-naphthalimide as a potent multi-target antitumor agent with good efficacy, limited toxicity, and low resistance

Discovery of 4-(N-dithiobenzyl piperazine)-1,8-naphthalimide as a potent multi-target antitumor agent with good efficacy, limited toxicity, and low resistance

  • Eur J Med Chem. 2023 Nov 10:263:115937. doi: 10.1016/j.ejmech.2023.115937.
Si-Min Liang 1,  Gui-Bin Liang 1,  Hui-Ling Wang 1,  Hong Jiang 1,  Xian-Li Ma 1,  Jian-Hua Wei 2,  Ri-Zhen Huang 3,  Ye Zhang 4
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Key Laboratory of Medical Biotechnology and Translational Medicine, School of Pharmacy, Guilin Medical University, Guilin, 541004, China.
  • 2 Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Key Laboratory of Medical Biotechnology and Translational Medicine, School of Pharmacy, Guilin Medical University, Guilin, 541004, China. Electronic address: weijh1124@glmc.edu.cn.
  • 3 Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Key Laboratory of Medical Biotechnology and Translational Medicine, School of Pharmacy, Guilin Medical University, Guilin, 541004, China. Electronic address: rzhuang1783@163.com.
  • 4 Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Key Laboratory of Medical Biotechnology and Translational Medicine, School of Pharmacy, Guilin Medical University, Guilin, 541004, China. Electronic address: zhangye81@126.com.
PMID: 37972528 DOI: 10.1016/j.ejmech.2023.115937
Abstract

A series of 4-(N-dithiobenzyl piperazine)-1,8-naphthalimide derivatives 4-6 were designed, synthesized, and evaluated as novel multi-target antitumor agents. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) results showed that compounds 5j, 5k, and 6j exhibited superior in vitro antiproliferative activity in MGC-803, HepG-2, SKOV-3, and T24 Cancer cell lines and the cisplatin-resistant cell line A549/DDP. HepG-2, SKOV-3, and T24 xenograft assay results revealed that compounds 5j, 5k, and 6j exhibited good antitumor effects compared with amonafide. The pathology results indicated that compound 5j exhibited the least comprehensive toxicity among the three compounds, identifying compound 5j as a good candidate antitumor agent with good efficacy, limited toxicity, and low resistance. Compound 5j was thus chose for further antitumor mechanism investigation. Results from the omics research, confocal immunofluorescence, Western blot, transmission electron microscopy, and flow cytometry indicated that compound 5j exerted antitumor effects through multiple mechanisms, including Ferroptosis, Autophagy, Apoptosis, and cell cycle arrest. These results suggest that screening novel 1,8-naphthalimide-based antitumor agents for good efficacy, limited toxicity, and low resistance based on a multi-target drug strategy is feasible.

Keywords

1,8-Naphthalimide; Apoptosis; Autophagy; Ferroptosis; Multi-targeting antitumor agent.

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