环氧合酶-2/5-脂氧合酶(COX-2/5-LOX)双重抑制剂吲哚-2-酰胺衍生物的合成及其抗增殖活性

doi:10.6023/cjoc202007073

摘要/Abstract

设计并合成了一系列新的吲哚-2-酰胺衍生物作为环氧合酶-2/5-脂氧合酶(COX-2/5-LOX)双重抑制剂, 并评估了它们的抗增殖活性. 其中, (5-氯-1-(4-氟苄基)-1H-吲哚-2-基)(4-(4-甲氧基苄基)哌嗪-1-基)甲酮(12h)对人结肠癌细胞(HCT-116)、人胃癌细胞(SGC-7901)和人非小细胞肺癌细胞(A549)的抑制活性强于塞来昔布; (5-氯-1-(4-甲氧基苄基)-1H-吲哚-2-基)(4-(4-甲氧基苄基)哌嗪-1-基)甲酮(7b)对A549 (IC₅₀=6.47 μmol?L ^–1)和HCT-116 (IC₅₀=13.80 μmol?L ^–1)细胞表现出显著的抗增殖活性. 化合物7b作为抗增殖实验中最具潜力的化合物, 显示出良好的COX-2 (IC₅₀=85.04 nmol?L^–1)和5-LOX (IC₅₀=125.3 nmol? L^–1)抑制活性. 对接分析表明, 吲哚环上的取代基有利于改善化合物与酶的亲和力. 进一步的研究证实7b可以剂量依赖性地诱导A549细胞凋亡.

关键词: 吲哚, 抗肿瘤, 环氧合酶(COX), 5-脂氧合酶(5-LOX), 对接

A novel series of indole-2-amide-derived cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) dual inhibitors were designed and synthesized, and biologically evaluated as anti-proliferative agents. Among them, (5-chloro-1-(4-fluoro- benzyl)-1H-indol-2-yl)(4-(4-methoxy-benzyl)piperazin-1-yl)methanone (12h) exhibited stronger inhibitory activity against three tumor strains of HCT-116, SGC-7901 and A549 than celecoxib, and (5-chloro-1-(4-methoxybenzyl)-1H-indol-2-yl)(4- (4-methoxybenzyl)piperazin-1-yl)methanone (7b) displayed outstanding anti-proliferative activity against A549 (IC₅₀=6.47 μmol?L ^–1) and HCT-116 (IC₅₀=13.80 μmol?L ^–1) cell lines. As the most potent compound in anti-proliferative assay, 7b demonstrated attractive COX-2 (IC₅₀=85.04 nmol?L^–1) and 5-LOX (IC₅₀=125.3 nmol?L^–1) inhibitory activities. As revealed by the docking analysis, the substituents on the indole ring were beneficial for improving the binding affinity to the enzyme. Further investigation confirmed that 7b could induce the apoptosis of A549 cells in a dose-dependent manner.

Key words: indole, anti-tumor, cyclooxygenase (COX), 5-lipoxygenase (5-LOX), docking

引用此文

钱诗虎, 黄元政, 李家明, 张艳春, 张斌, 金凡. 环氧合酶-2/5-脂氧合酶(COX-2/5-LOX)双重抑制剂吲哚-2-酰胺衍生物的合成及其抗增殖活性[J]. 有机化学, 2021, 41(4): 1631-1638.

Shihu Qian, Yuanzheng Huang, Jiaming Li, Yanchun Zhang, Bin Zhang, Fan Jin. Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors[J]. Chinese Journal of Organic Chemistry, 2021, 41(4): 1631-1638.

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参考文献 18

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Compd.	IC₅₀^a^,^b/(μmol?L^–1)
Compd.	HCT-116	SGC-7901	A549
Celecoxib	37.63±2.14	48.73±3.29	22.23±1.89
5-FU	20.23±1.26	40.20±2.76	44.32±3.26
12h	22.32±0.30	26.98±1.67	13.72±0.61
7a	92.26±6.28	66.62±4.55	89.02±5.61
7b	13.80±1.05	90.79±6.59	6.47±0.43
7c	39.93±2.67	106.80±7.18	31.94±2.17
7d	101.90±6.97	46.79±2.62	114.20±7.86
7e	83.10±5.21	36.86±2.37	53.78±3.64
7f	17.63±1.17	66.33±4.18	32.35±2.04
7g	101.40±7.62	100.00±7.93	70.10±3.78
7h	169.30±13.45	85.16±5.67	207.90±12.38
7i	160.80±11.69	123.50±10.09	68.14±3.76
7j	150.30±±10.15	197.30±14.66	357.80±19.98
7k	39.23±2.15	100.50±7.84	35.48±2.67
7l	142.70±11.98	362.80±20.11	121.00±8.27
7m	90.71±6.55	60.98±4.16	143.60±8.91

Compd.	IC₅₀^a^,^b/(μmol?L^–1)
Compd.	HCT-116	SGC-7901	A549
Celecoxib	37.63±2.14	48.73±3.29	22.23±1.89
5-FU	20.23±1.26	40.20±2.76	44.32±3.26
12h	22.32±0.30	26.98±1.67	13.72±0.61
7a	92.26±6.28	66.62±4.55	89.02±5.61
7b	13.80±1.05	90.79±6.59	6.47±0.43
7c	39.93±2.67	106.80±7.18	31.94±2.17
7d	101.90±6.97	46.79±2.62	114.20±7.86
7e	83.10±5.21	36.86±2.37	53.78±3.64
7f	17.63±1.17	66.33±4.18	32.35±2.04
7g	101.40±7.62	100.00±7.93	70.10±3.78
7h	169.30±13.45	85.16±5.67	207.90±12.38
7i	160.80±11.69	123.50±10.09	68.14±3.76
7j	150.30±±10.15	197.30±14.66	357.80±19.98
7k	39.23±2.15	100.50±7.84	35.48±2.67
7l	142.70±11.98	362.80±20.11	121.00±8.27
7m	90.71±6.55	60.98±4.16	143.60±8.91

Compd.	IC₅₀^a/(nmol?L^–1)
Compd.	COX-1	COX-2
7a	916.4±134.9	130.9±6.14
7b	897.0±30.18	85.04±5.71
7c	678.5±88.60	614.2±91.72
7d	766.2±188.9	321.5±89.94
7e	1334.7±173.8	365.3±77.71
7f	1128.0±50.89	312.4±15.77
7g	1128.5±184.8	370.5±46.50
7h	1920.2±95.86	337.6±36.12
7i	1407.1±489.2	734.0±194.7
7j	1390.5±317.8	559.3±61.22
7k	1550.1±317.3	335.2±33.87
7l	1289.6±240.8	865.1±140.3
7m	2670.3±285.4	365.8±108.8
Celecoxib	14993±794.5	11.1±0.79

Compd.	IC₅₀^a/(nmol?L^–1)
Compd.	COX-1	COX-2
7a	916.4±134.9	130.9±6.14
7b	897.0±30.18	85.04±5.71
7c	678.5±88.60	614.2±91.72
7d	766.2±188.9	321.5±89.94
7e	1334.7±173.8	365.3±77.71
7f	1128.0±50.89	312.4±15.77
7g	1128.5±184.8	370.5±46.50
7h	1920.2±95.86	337.6±36.12
7i	1407.1±489.2	734.0±194.7
7j	1390.5±317.8	559.3±61.22
7k	1550.1±317.3	335.2±33.87
7l	1289.6±240.8	865.1±140.3
7m	2670.3±285.4	365.8±108.8
Celecoxib	14993±794.5	11.1±0.79

Compd.	IC₅₀^a/(nmol?L^–1)
7a	626.9±45.18
7b	125.3±7.04
7c	65.37±4.15
7d	467.6±30.54
7e	471.5±33.27
7f	33.1±1.83
7g	679±42.63
7h	226.1±12.58
7i	655.3±39.67
7j	827±62.73
7k	531.4±29.11
7l	101±8.57
7m	314.3±23.19
Zileuton	39.7±2.31