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

doi:10.6023/cjoc202504032

有机化学 ›› 2026, Vol. 46 ›› Issue (1): 250-265.DOI: 10.6023/cjoc202504032 上一篇下一篇

研究论文

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^†, 徐浩^†, 周华锋, 王夏洁, 李培源, 夏星, 陈文雅^*(), 霍丽妮^*()

广西中医药大学药学院南宁 530222

收稿日期:2025-04-28 修回日期:2025-07-01 发布日期:2025-08-26
通讯作者: 陈文雅, 霍丽妮
作者简介:
^† 共同第一作者
基金资助:
国家自然科学基金(22567007); 国家自然科学基金(22067001); 广西自然科学基金(2023GXNSFAA026476); 广西药物发现与优化重点实验室(GKLPM-DDO2022B02); 广西中医药大学研究生教育创新计划(YCSW2024425); 广西中医药大学“岐黄工程”高层次人才团队培育项目(202405); 桂派中医药传承创新团队(2022B005); 广西中医药大学“桂派中医药传承创新团队”项目及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(GXZYYZZ2023-08)

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

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

Institute of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530222

Received:2025-04-28 Revised:2025-07-01 Published:2025-08-26
Contact: Chen Wenya, Huo Lini
About author:
^† The authors contributed equally to this work
Supported by:
National Natural Science Foundation of China(22567007); National Natural Science Foundation of China(22067001); Natural Science Foundation of Guangxi Province(2023GXNSFAA026476); Project Program of Guangxi Key Laboratory of Drug Discovery and Optimization(GKLPM-DDO2022B02); Innovation Project of Guangxi Graduate Education of Guangxi University of Chinese Medicine(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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摘要/Abstract

利用Heck反应设计合成了一系列基于氯化两面针碱(NC)母核的新型含氮杂环化合物, 包括磺酰胺类衍生物、哌嗪类衍生物及噻唑类衍生物. 通过体外细胞毒性实验, 评估了目标化合物对四种肿瘤细胞株(HL-60、HeLa、HepG2、H460)及正常肝细胞(LO2)增殖的抑制活性. 结果显示, 磺酰胺类衍生物对HeLa细胞表现出选择性抑制作用. 其中, 2,4,6-三甲基-N-[6-(6-氧代苯并[c]菲啶-5(6H)-基)己基]苯磺酰胺(14c)活性最强[IC₅₀=(1.83±0.24) μmol/L], 其活性与氯化两面针碱及顺铂相当, 且对正常LO2细胞无明显毒性. 哌嗪类衍生物对多数测试肿瘤细胞具有抑制作用, 但同时也具有一定的细胞毒性, 噻唑类衍生物则基本无活性. 作用机制研究表明, 代表性化合物14c通过诱导HeLa细胞凋亡及周期阻滞发挥抗肿瘤作用, 其特征为G0/G1期细胞比例显著降低(69.90%±5.80%)并促进S/G2/M期进程. 拓扑异构酶I (Topo I)抑制实验表明, 哌嗪衍生物能够有效抑制Topo I的活性. 综上, 化合物14c可作为高效低毒的抗肿瘤候选化合物, 表明两面针碱的含氮杂化修饰是研究开发新型Topo I抑制剂潜在的有效途径.

关键词: 氯化两面针碱, 抗肿瘤, DNA拓扑异构酶I, 细胞周期, 细胞凋亡

A series of novel nitrogen-containing heterocyclic compounds based on the nitidine chloride (NC) core were designed and synthesized through the Heck reaction. The derivatives included sulfonamide analogs, piperazine analogs, and thiazole analogs. 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, 2,4,6-trimethyl-N-(6-(6-oxobenzo[c]phenanthridin-5(6H)-yl)hexyl)benzenesulfonamide (14c) exhibited the most potent activity [IC₅₀=(1.83±0.24) μmol/L], 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. The topoiso-merase I (Topo I) inhibition assay demonstrated that the piperazine derivative effectively inhibits Topo I activity. Overall, compound 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

引用此文

粟晓微, 徐浩, 周华锋, 王夏洁, 李培源, 夏星, 陈文雅, 霍丽妮. 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[J]. 有机化学, 2026, 46(1): 250-265.

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, 2026, 46(1): 250-265.

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图/表 11

Figure 1. Structures of nitidine chloride and its analogues

Figure 2. Design of hybrids tetracyclic skeleton of nitidine and nitrogen-containing functional groups

Scheme 1. Synthetic routes of tetracyclic analogue skeletons of nitidine (6 and 7) Reagents and conditions: (a) N2, oxalyl chloride, DCM, r.t.; (b) 1-naphthylamine, dichloromethane (DCM), triethylamine (TEA), r.t.; (c) 1,4- dibromobutane or 1,6-dibromohexane, NaH, DMF, r.t.; (d) N2, Pd(OCOCH3)2, tri(o-tolyl)phosphine, Ag2O, EtOAc, reflux.

Scheme 2. Synthetic routes of nitrogen-containing derivatives based on nitidine skeletons Reagents and conditions: (a) phthalimide, KI, K2CO3, CH3CN, reflux; (b) 40% methylamine, r.t.; (c) TEA, DCM, r.t.; (d) KI, K2CO3, CH3CN, 60 ℃, reflux.

Entry	Temp./℃	Time/h	Catalyst/mmol	Solvent	Yield/%
1	120	24	0.2	DMF	67.6
2	100	24	0.2	DMF	66.3
3	80	24	0.2	DMF	66.4
4	60	24	0.2	DMF	67.1
5	40	24	0.2	DMF	45.9
6	60	12	0.2	DMF	65.9
7	60	6	0.2	DMF	65.7
8	60	3	0.2	DMF	65.4
9	60	1.5	0.2	DMF	55.2
10	60	3	0.1	DMF	65.3
11	60	3	0.05	DMF	35.3
12	60	3	0.1	EtOAc	71.3

Table 1. Effect of various influencing factors on yield of cyclization product 6

Compd.	HL-60	HeLa	HepG2	H460	LO2
13a	>40	19.47±0.19	>40	>40	>40
13b	>40	>40	>40	>40	>40
13c	>40	>40	>40	>40	>40
13d	>40	>40	>40	>40	>40
13e	>40	11.75±1.16	>40	>40	>40
14a	>40	9.27±1.45	>40	>40	>40
14b	>40	7.39±0.24	>40	>40	>40
14c	>40	1.83±0.24	>40	>40	>40
14d	0.96±0.01	17.48±2.80	>40	>40	1.07±0.10
14e	>40	4.20±0.12	>40	>40	>40
16a	>40	4.89±0.42	>40	>40	>40
16b	>40	19.35±0.48	>40	>40	>40
16c	>40	>40	>40	>40	>40
16d	>40	>40	>40	>40	>40
16e	16.47±0.48	14.69±0.49	19.97±0.12	19.82±0.52	27.15±1.13
16f	13.78±0.09	9.62±0.51	14.54±0.15	>40	16.23±0.19
16g	>40	>40	>40	>40	>40
16h	13.29±0.11	10.35±0.67	14.24±0.53	17.61±0.12	15.69±0.02
17a	>40	>40	>40	>40	>40
17b	7.38±0.33	5.03±0.38	16.76±0.16	16.66±0.25	16.63±0.12
17c	>40	>40	>40	>40	>40
17d	9.68±0.46	>40	>40	>40	>40
17e	>40	14.48±0.11	16.04±0.24	16.88±0.41	15.90±0.23
17f	16.70±0.92	3.47±0.10	10.52±0.28	4.657±0.07	11.13±0.06
17g	10.22±0.51	18.55±0.50	>40	>40	25.17±0.31
17h	12.92±0.65	7.59±0.84	17.09±0.13	17.25±0.29	16.10±0.17
19a	>40	>40	>40	>40	>40
19b	>40	>40	>40	>40	>40
19c	>40	>40	>40	>40	>40
20a	>40	>40	>40	>40	>40
20b	>40	>40	>40	>40	>40
20c	>40	>40	>40	>40	>40
NC	13.47±0.38	1.48±0.11	3.41±0.09	3.37±0.22	4.10±0.11
cisplatin	2.44±0.08	2.01±0.14	3.86±0.15	15.08±0.39	8.65±0.10

Table 2. IC50 values (μmol/L) of the synthesized compounds obtained for anti-proliferative activity on different tumor cell lines

Figure 3. DNA Topo I inhibitory activity of compounds at concentration of 1 mmol/L (using CPT and NC as positive controls)

Figure 4. The best pose of the binding mode of compounds 14c and 16h with DNA Topo I complex (PDB:1T8I)

Figure 5. Morphological observation of 14c with Hoechst 33258 staining under fluorescence microscope (A) HeLa cells line treated with only 5% DMSO solution (control); (B) Nitidine chloride treated at concentrations of 1.48 μmol/L; (C, D and E) Compound 14c treated at concentrations of 1.83, 9.15 and 18.3 μmol/L, respectively

Figure 6. Apoptosis ratio detection of compound 14c by FITC and PI assay (A) HeLa cells line treated with 8% DMSO for 24 h used as control; (B) Treament with NC at 1.83 μmol/L for 24 h; (C, D and E) Treament with compound 14c at 1.83, 9.15 and 18.3 μmol/L for 24 h, respectively; (F) Percentage of quadrants Q2 and Q4 expressed as mean±standard errors (n=3, ***p<0.05)

Figure 7. Cell-cycle analysis by flow cytometry of HeLa cells line treated with compound 14c (A) HeLa cells line treated with 8% DMSO for 24 h used as control; (B) Treament with NC at 1.83 μmol/L for 24 h; (C, D and E) Treament with compound 14c at 1.83, 9.15 and 18.3 μmol/L for 24 h, respectively; (F) The percentages of each population are expressed as mean±standard erros (n=3, *p<0.05)

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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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