以环丙烷限制构象的新型双酰胺的设计、合成、抗癌活性及计算分析

doi:10.6023/cjoc202106053

摘要/Abstract

为了探索具有新型骨架的抗癌剂, 设计了一系列的以环丙烷限制构象的双酰胺类化合物. 大多数含有顺式环丙烷中心的外消旋体对四种肿瘤细胞系(MCF-7、BGC-823、HepG2和NCI-H460)具有良好的抑制活性. 其中, 消旋体顺式-N¹-(2-甲基-4-(全氟丙-2-基)苯基)-N²-(4-苯氧基苄基)环丙烷-1,2-二羧酰胺(1-19)对MCF-7的IC₅₀值为(8.38±0.67) mg•L^–1, 显示出可进一步优化为抗癌先导物的潜力. 此外, 甾醇硫酸酯酶(steryl-sulfatase, STS)被PharmMapper预测为可能的靶标蛋白, 并由分子对接实验进行了验证.

关键词: 双酰胺, 环丙烷, 抗癌活性, 靶标预测, 分子对接

A series of diamides conformationally restricted by cyclopropane were designed and synthesized. Most of the racemates containing cis-cyclopropane possessed promising inhibitory activity against four cancer cell lines (MCF-7, BGC-823, HepG2 and NCI-H460). In particular, racemate cis-N¹-(2-methyl-4-(perfluoropropan-2-yl)phenyl)-N²-(4-phenoxy- benzyl)cyclopropane-1,2-dicarboxamide (1-19) showed the potential for further optimization as an anti-cancer lead with the IC₅₀ value of (8.38±0.67) mg•L^–1 on MCF-7. Moreover, steryl-sulfatase (STS) was predicated as the potential target protein and molecular docking was performed to explore the binding mode.

Key words: diamides, cyclopropane, anti-cancer activities, target prediction, docking

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陈睿嘉, 周聪, 逄锡文, 刘佳君, 顾玉诚, 刘建文, 李忠. 以环丙烷限制构象的新型双酰胺的设计、合成、抗癌活性及计算分析[J]. 有机化学, 2022, 42(1): 277-292.

Ruijia Chen, Cong Zhou, Xiwen Pang, Jiajun Liu, Yucheng Gu, Jianwen Liu, Zhong Li. Design, Synthesis, Anti-cancer Activities and Computational Analysis of Novel Diamides Conformationally Restricted by Cyclopropane[J]. Chinese Journal of Organic Chemistry, 2022, 42(1): 277-292.

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Compd.	Structure (Relative stereochemistry)	Growth-inhibition (200 μg•mL^–1)
Compd.	Structure (Relative stereochemistry)	MCF-7	BGC-823	HepG2	NCI-H460
1-2		83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-31		19.42±1.19	–28.92±2.03	38.24±5.37	14.20±6.58

Compd.	Structure (Relative stereochemistry)	Growth-inhibition (200 μg•mL^–1)
Compd.	Structure (Relative stereochemistry)	MCF-7	BGC-823	HepG2	NCI-H460
1-2		83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-31		19.42±1.19	–28.92±2.03	38.24±5.37	14.20±6.58

Compd.	R¹	Growth-inhibition (200 μg•mL^–1)
Compd.	R¹	MCF-7	BGC-823	HepG2	NCI-H460
1-1	Methyl	37.23±3.34	32.39±1.17	23.47±4.79	47.37±0.50
1-2	Ethyl	83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-3	tert-Butyl	85.73±2.92	4.17±0.52	57.57±1.57	94.34±2.25
1-4	Benzyl	96.83±0.69	97.75±0.08	99.14±0.28	98.42±0.16
1-30	Phenethyl	90.96±0.28	91.19±0.99	93.00±8.44	97.46±0.16

Compd.	R¹	Growth-inhibition (200 μg•mL^–1)
Compd.	R¹	MCF-7	BGC-823	HepG2	NCI-H460
1-1	Methyl	37.23±3.34	32.39±1.17	23.47±4.79	47.37±0.50
1-2	Ethyl	83.46±3.64	54.78±1.16	48.13±1.69	97.31±0.18
1-3	tert-Butyl	85.73±2.92	4.17±0.52	57.57±1.57	94.34±2.25
1-4	Benzyl	96.83±0.69	97.75±0.08	99.14±0.28	98.42±0.16
1-30	Phenethyl	90.96±0.28	91.19±0.99	93.00±8.44	97.46±0.16

Compd.	R¹	IC₅₀/(μg•mL^–1)
Compd.	R¹	MCF-7	BGC-823	HepG2	NCI-H460
1-1	Methyl	>200	>200	>200	>200
1-2	Ethyl	33.81±2.06	>200	>200	29.80±2.91
1-3	tert-Butyl	29.27±5.83	>200	>200	38.38±1.40
1-4	Benzyl	40.79±2.18	50.90±0.99	26.09±2.97	26.78±2.78
1-5	4-Methylbenzyl	32.29±1.7	21.25±3.03	10.44±1.60	20.38±1.21
1-6	3-Methylbenzyl	40.35±5.19	35.50±3.97	35.01±1.54	30.59±1.18
1-7	2-Methylbenzyl	33.80±1.72	25.42±2.29	23.20±1.07	21.60±1.60
1-8	4-Chlorobenzyl	36.89±2.29	19.47±5.37	17.65±1.24	10.06±1.82
1-9	3-Chlorobenzyl	36.80±4.39	30.58±2.65	28.62±0.81	22.48±0.71
1-10	2-Chlorobenzyl	80.47±6.93	31.75±4.74	22.75±0.84	21.61±1.30
1-11	4-Fluorobenzyl	67.45±2.43	29.55±2.70	27.07±1.05	25.27±2.85
1-12	4-Bromobenzyl	17.65±0.99	28.29±2.54	21.17±0.81	21.01±1.25
1-13	4-Iodobenzyl	27.57±6.26	26.24±2.70	26.29±1.43	26.15±1.36
1-14	4-Methoxybenzyl	20.78±1.38	24.51±2.57	24.14±1.23	25.17±1.84
1-15	4-Difluoromethoxybenzyl	75.61±14.80	50.03±2.97	39.52±6.27	56.80±10.58
1-16	4-tert-Butylbenzyl	>200	92.61±16.39	>200	95.35±17.62
1-17	4-Cyanobenzyl	47.75±9.06	42.49±4.12	37.92±2.94	30.26±3.15
1-18	4-Trifluoromethylbenzyl	25.66±1.11	21.39±1.11	21.23±1.99	15.12±1.43
1-19	(4-Phenoxyphenyl)methyl	8.38±0.67	22.67±0.80	19.30±1.10	20.49±1.32
1-20	4-Phenylbenzyl	25.88±2.95	24.97±1.27	27.06±3.07	22.94±1.15
1-21	2,4-Difluorobenzyl	40.84±1.24	51.29±1.09	23.52±2.50	28.35±2.28
1-22	2,6-Dichlorobenzyl	>200	>200	19.74±0.79	39.89±9.27
1-23	3,4,5-Trimethoxybenzyl	19.16±3.01	34.39±3.52	27.22±2.61	20.39±1.41
1-24	(Tetrahydrofuran-3-yl)methyl	153.9±20.2	50.30±6.65	46.88±5.39	56.51±11.21
1-25	(6-Chloropyridine-3-yl)methyl	27.12±0.92	32.39±3.46	34.15±0.94	29.36±1.79
1-26	(2-Chlorothiazole-5-yl)methyl	>200	>200	>200	>200
1-27	Furan-2-ylmethyl	25.8±1.32	32.39±4.40	15.42±4.40	27.03±2.49
1-28	Thiophene-3-ylmethyl	83.43±4.37	>200	>200	>200
1-29	Naphthalene-1-ylmethyl	32.53±2.82	22.91±1.20	23.55±1.97	20.52±0.98
1-30	Phenethyl	59.05±3.60	53.12±1.16	26.76±1.18	30.37±2.36
5-Fu	—	8.23±1.33	10.31±1.40	7.09±1.61	2.26±0.80