Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors

doi:10.6023/cjoc202007073

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (4): 1631-1638.DOI: 10.6023/cjoc202007073 Previous Articles Next Articles

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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

钱诗虎^a, 黄元政^a, 李家明^a^,^b^,^*(), 张艳春^a^,^b, 张斌^a, 金凡^a

a 安徽中医药大学药学院合肥 230031
b 安徽省中医药科学院药物化学研究所合肥 230031

收稿日期:2020-07-31 修回日期:2020-10-23 发布日期:2020-12-19
通讯作者: 李家明

Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors

Shihu Qian^a, Yuanzheng Huang^a, Jiaming Li^a^,^b^,^*(), Yanchun Zhang^a^,^b, Bin Zhang^a, Fan Jin^a

a School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230031
b Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230031

Received:2020-07-31 Revised:2020-10-23 Published:2020-12-19
Contact: Jiaming Li
About author:
* Corresponding author. E-mail: lijiaming2017@sina.com

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Abstract

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

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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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Fig. & Tab. 8

References 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

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

Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors

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