新型喹啉-吲哚衍生物的设计、合成及抗肿瘤活性研究

doi:10.6023/cjoc202103059

有机化学 ›› 2021, Vol. 41 ›› Issue (9): 3617-3624.DOI: 10.6023/cjoc202103059 上一篇下一篇

研究论文

新型喹啉-吲哚衍生物的设计、合成及抗肿瘤活性研究

王胜辉^a, 关永风^b, 刘秀娟^c, 原信颖^c, 蔚广曦^a, 李银茹^a, 张雁冰^c, 宋健^a^,^c^,^*(), 李雯^b^,^c^,^*(), 张赛扬^a^,^c^,^*()

a 郑州大学基础医学院郑州 450001
b 郑州大学化工学院郑州 450001
c 郑州大学药学院郑州 450001

收稿日期:2021-03-30 修回日期:2021-05-25 发布日期:2021-06-29
通讯作者: 宋健, 李雯, 张赛扬
作者简介:
† 共同第一作者.
基金资助:
国家自然科学基金(81703541); 国家自然科学基金(81673322); 国家自然科学基金(U2004123); 中国博士后科学基金(2018M632812)

Design, Synthesis and Anticancer Activity Studies of Novel Quinoline-Indole Derivatives

Shenghui Wang^a, Yongfeng Guan^b, Xiujuan Liu^c, Xinying Yuan^c, Guangxi Yu^a, Yinru Li^a, Yanbing Zhang^c, Jian Song^a^,^c(), Wen Li^b^,^c(), Saiyang Zhang^a^,^c()

a School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001
b School of Chemical Engineering, Zhengzhou University, Zhengzhou 450001
c School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001

Received:2021-03-30 Revised:2021-05-25 Published:2021-06-29
Contact: Jian Song, Wen Li, Saiyang Zhang
About author:
† These authors contributed equally to this work.
Supported by:
National Natural Science Foundation of China(81703541); National Natural Science Foundation of China(81673322); National Natural Science Foundation of China(U2004123); China Postdoctoral Science Foundation(2018M632812)

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摘要/Abstract

作为开发新型有效抗癌药物的进一步工作, 采用分子杂交策略和路易斯酸催化偶联反应设计合成了一系列新型喹啉-吲哚类化合物. 使用噻唑蓝(MTT)法评估了所合成的化合物对人胃癌细胞(MGC-803)、人食管癌细胞(Kyse450)和人结肠癌细胞(HCT-116)的体外抑制活性. 其中, 2-氯-4-(5-甲氧基-1H-吲哚-3-基)喹啉(9b)展示较好的体外抗肿瘤活性, 对MGC-803、Kyse450和HCT-116三种人源癌细胞IC₅₀值分别为0.58, 0.60和0.68 µmol•L^–1, 优于阳性对照药5-氟尿嘧啶(5-Fu)对这三种肿瘤细胞的抑制活性. 进一步机制研究表明, 化合物9b能够剂量依赖地抑制人胃癌细胞MGC-803和HGC-27的增殖和克隆形成. 化合物9b能够诱导人胃癌细胞MGC-803和HGC-27内源性凋亡和下调相关凋亡蛋白的表达, 并使细胞周期阻滞在G2/M期. 以上结果表明, 化合物9b可以作为先导化合物, 用于进一步研究开发新型高效抗肿瘤药物.

关键词: 喹啉, 吲哚, 抗肿瘤活性, 增值, 凋亡, 细胞周期阻滞

As the continuation of our studies on novel and effective anti-cancer agents, a series of novel quinoline-indole derivatives were firstly designed and synthesized by molecular hybridization strategy and Lewis acid‐catalyzed coupling reactions. Their antiproliferative potency on gastric cancer cell line MGC-803, colon cancer cell line HCT-116, and esophageal cancer cell line Kyse450 of all the targeted compounds was explored using methyl thiazolyl tetrazolium (MTT) assay. 2-Chloro-4-(5-methoxy-1H-indol-3-yl)quinoline (9b) exhibited potently inhibitory activity against MGC-803, HCT-116, and Kyse450 cells with IC₅₀ values of 0.58, 0.68 and 0.59 µmol•L^–1. Further mechanism studies suggested that compound 9b inhibited the cell colony formation of MGC-803 and HGC-27 cells. Compound 9b induced an intrinsic apoptosis and down- regulated the levels of apoptosis related proteins in MGC-803 and HGC-27 cells. Meanwhile, compound 9b arrested MGC-803 and HGC-27 cells at the G2/M phase. Taken together, these results indicated that compound 9b might be a valuable lead compound for anticancer agents.

Key words: quinoline, indole, anticancer activity, proliferation, apoptosis, cell cycle arrest

引用此文

王胜辉, 关永风, 刘秀娟, 原信颖, 蔚广曦, 李银茹, 张雁冰, 宋健, 李雯, 张赛扬. 新型喹啉-吲哚衍生物的设计、合成及抗肿瘤活性研究[J]. 有机化学, 2021, 41(9): 3617-3624.

Shenghui Wang, Yongfeng Guan, Xiujuan Liu, Xinying Yuan, Guangxi Yu, Yinru Li, Yanbing Zhang, Jian Song, Wen Li, Saiyang Zhang. Design, Synthesis and Anticancer Activity Studies of Novel Quinoline-Indole Derivatives[J]. Chinese Journal of Organic Chemistry, 2021, 41(9): 3617-3624.

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图/表 8

Figure 1. Structures of quinoline derivatives as anticancer agents previously reported

Figure 2. Structures of indole derivatives as anticancer agents previously reported

Scheme 1. Design of novel quinoline-indole as anticancer agents via molecular hybridization

Scheme 2. Synthesis and structures of the target compounds 9a~9j

Compound	IC₅₀/(μmol•L^–1)^a
Compound	MGC-803	Kyse450	HCT-116
9a	3.91±0.22	3.27±0.18	3.11±0.16
9b	0.58±0.01	0.68±0.03	0.59±0.04
9c	4.10±0.21	5.17±0.53	8.23±0.42
9d	2.86±0.19	6.78±1.04	6.01±0.37
9e	4.34±0.44	4.68±0.24	5.91±0.38
9f	7.00±0.82	5.27±0.34	11.1±1.41
9g	2.42±0.12	3.04±0.23	2.87±0.21
9h	1.16±0.05	1.40±0.12	1.71±0.19
9i	>20	>20	>20
9j	4.58±0.25	6.57±0.21	5.06±0.33
5-Fu	6.82±0.82	17.4±1.23	14.2±1.22

Table 1. In vitro antiproliferative activity of compounds 9a~9j against MGC-803, HCT-116 and Kyse450 cells

Figure 3. Compound 9b inhibited gastric cancer cells in vitro (A) Cell viability of 2 gastric cancer cells after the treatment with indicated concentrations of 9b for 48 h; (B, C) Growth curves of gastric cancer cells after the treatment with indicated concentrations of 9b for 72 h; (D, E) Cell morphology changes. Cells were treated with different concentrations of compound 9b for 48 h, then the images were captured in a bright field or after stained by DAPI or Calcein-AM/PI.

Figure 4. Compound 9b induced cell apoptosis (A~D) Cell apoptosis analysis after the treatment with indicated concentrations of compound 9b for 48 h; (E, F) Levels of intrinsic apoptosis related proteins in 2 gastric cancer cells. Cells were treated with indicated concentrations of compound 9b for 48 h.

Figure 5. Compound 9b inhibited the cell proliferation (A) Colony formatting analysis, cells were incubated with indicated concentrations of compound 9b for 7 d; (B~E) Cell cycle distribute analysis, cells were treated indicated concentrations of compound 9b for 48 h; (F~H) Cell cycle related proteins in 2 gastric cancer cells. Cells were treated with indicated concentrations of compound 9b for 48 h.

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新型喹啉-吲哚衍生物的设计、合成及抗肿瘤活性研究

Design, Synthesis and Anticancer Activity Studies of Novel Quinoline-Indole Derivatives

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