Design, Synthesis and Anticancer Activity Evaluation of Novel Nitrogen-containing Heterocyclic Compounds Based on Nitidine Skeleton

doi:10.6023/cjoc202504032

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基于两面针碱骨架的新型含氮杂环化合物设计、合成及抗肿瘤活性评价

粟晓微^†,a, 徐浩^†,a, 周华锋^a, 王夏洁^a, 李培源^a, 夏星^a, 陈文雅^a,*, 霍丽妮^a,*

^a广西中医药大学药学院广西南宁 530222

收稿日期:2025-04-28 修回日期:2025-07-01
基金资助:
国家自然科学基金项目（22067001）、广西自然科学基金项目（2023GXNSFAA026476）、广西药物发现与优化重点实验室项目（GKLPMDDO2022B02）、广西中医药大学研究生教育创新计划项目（YCSW2024425）、广西中医药大学“岐黄工程”高层次人才团队培育项目（202405）、广西中医药大学“桂派中医药传承创新团队”项目、广西壮瑶药物实验室2023重点实验室（壮瑶药物实验室协同创新中心）自主研究项目（GXZYYZZ2023-08）资助项目.

Design, Synthesis and Anticancer Activity Evaluation of Novel Nitrogen-containing Heterocyclic Compounds Based on Nitidine Skeleton

Su Xiaowei^†,a, Xu Hao^†,a, Zhou Huafeng^a, Wang Xiajie^a, Li Peiyuan^a, Xia Xing^a, Chen Wenya^a,*, Huo Lini^a,*

^aInstitute of pharmacy, Guangxi University of Chinese Medicine, Nanning,GuangXi 530222

Received:2025-04-28 Revised:2025-07-01
Contact: * E-mail: 364874916@qq.com and huolini@126.com
Supported by:
National Natural Science Foundation of China (22067001), Natural Science Foundation of Guangxi Province (2023GXNSFAA026476), the Project Program of Guangxi Key Laboratory of Drug Discovery and Optimization (GKLPMDDO2022B02), Innovation Project of Guangxi Graduate Education of GXUCM(YCSW2024425), Qihuang High-level Talent Team Cultivation Project of Guangxi University of Chinese Medicine (202405), Inheritance and Innovation team of Guangxi Traditional Chinese Medicine (2022B005), 2023 Key Laboratory of Guangxi Zhuang and Yao Medicinal Laboratory (Collaborative Innovation Center for Zhuang and Yao Medicinal Laboratory) Independent Research Project (GXZYYZZ2023-08).

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Abstract

This study designed and synthesized a series of novel nitrogen-containing heterocyclic compounds based on the nitidine chloride (NC) core through the Heck reaction. The derivatives included sulfonamide analogs (13a-13e, 14a-14e), piperazine analogs (16a-16h, 17a-17h), and thiazole analogs (19a-19c, 20a-20c). Their antiproliferative activities were evaluated against four tumor cell lines (HL-60, HeLa, HepG2, H460) and normal liver cells (LO2) via in vitro cytotoxicity assays. The results showed that sulfonamide derivatives selectively inhibited HeLa cells. Among them, compound 14c exhibited the most potent activity (IC₅₀ = 1.83 ± 0.24 μM), comparable to nitidine chloride and cisplatin, while showing no significant toxicity toward LO2 cells. Piperazine analogs displayed broad inhibitory effects against tumor cells but accompanied by cytotoxicity, whereas thiazole analogs were largely inactive. Mechanistic studies revealed that the representative compound 14c exerted antitumor effects by inducing apoptosis and cell cycle arrest in HeLa cells, manifested by a significant reduction in the proportion of G0/G1 phase cells (69.90 ± 5.80%) and promotion of S/G2/M phase progression. Topoisomerase I (Topo I) inhibition assays indicated that piperazine derivatives exhibited distinctly different modes of direct Topo I inhibition. Overall, 14c emerges as a promising antitumor candidate with high efficacy and low toxicity, demonstrating that nitrogen-containing hybridization of nitidine chloride provides a potential strategy for developing novel Topo I inhibitors.

Key words: Nitidine chloride, Anticancer, DNA topoisomerase I, cell cycle, apoptotic

Cite this article

Su Xiaowei, Xu Hao, Zhou Huafeng, Wang Xiajie, Li Peiyuan, Xia Xing, Chen Wenya, Huo Lini. Design, Synthesis and Anticancer Activity Evaluation of Novel Nitrogen-containing Heterocyclic Compounds Based on Nitidine Skeleton[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202504032.

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基于两面针碱骨架的新型含氮杂环化合物设计、合成及抗肿瘤活性评价

Design, Synthesis and Anticancer Activity Evaluation of Novel Nitrogen-containing Heterocyclic Compounds Based on Nitidine Skeleton

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