2-[(吡啶-2-基甲基)硫基]-1H-苯并咪唑类化合物的设计、合成和抗癌活性研究

doi:10.6023/cjoc202201002

有机化学 ›› 2022, Vol. 42 ›› Issue (7): 2172-2183.DOI: 10.6023/cjoc202201002 上一篇下一篇

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2-[(吡啶-2-基甲基)硫基]-1H-苯并咪唑类化合物的设计、合成和抗癌活性研究

赵静^a, 金辄^a, 王润^a, 张新庚^a, 韩英妹^a, 胡春^a^,^*(), 刘晓平^a^,^*(), 张传明^a^,^b^,^*(), 金丽萍^c

^a沈阳药科大学教育部基于靶点的药物设计与研究重点实验室沈阳 110016
^b包头医学院药学院内蒙古包头 014040
^c锦州医科大学药学院辽宁锦州 121001

收稿日期:2022-01-02 修回日期:2022-02-26 发布日期:2022-08-09
通讯作者: 胡春, 刘晓平, 张传明
基金资助:
国家自然科学基金(21342006); 教育部创新团队(IRT_14R36)

Design, Synthesis and Anticancer Activity of 2-((Pyridin- 2-ylmethyl)thio)-1H-benzimidazole Derivatives

Jing Zhao^a, Zhe Jin^a, Run Wang^a, Xin'geng Zhang^a, Yingmei Han^a, Chun Hu^a(), Xiaoping Liu^a(), Chuanming Zhang^a^,^b(), Liping Jin^c

^aKey Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016
^bSchool of Pharmacy, Baotou Medical College, Baotou, Inner Mongolia 014040
^cCollege of Pharmacy, Jinzhou Medical University, Jinzhou, Liaoning 121001

Received:2022-01-02 Revised:2022-02-26 Published:2022-08-09
Contact: Chun Hu, Xiaoping Liu, Chuanming Zhang
Supported by:
National Natural Science Foundation of China(21342006); Program for Innovative Research Team of the Ministry of Education(IRT_14R36)

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1. 2-[(吡啶-2-基甲基)硫基]-1 H-苯并咪唑类化合物的设计、合成和抗癌活性研究.pdf(4699KB)

摘要/Abstract

苯并咪唑类化合物具有多种生物活性, 是一类重要的含氮杂环化合物. 合成了一系列具有全新结构的2-[(吡啶- 2-基甲基)硫代]-1H-苯并咪唑类化合物, 并采用噻唑蓝(MTT)比色法考察了化合物对人肺癌细胞株A549、人结直肠癌细胞株HCT116和人前列腺癌细胞株PC3的抑制活性. 结果表明, 部分目标化合物对上述癌细胞株具有较强的抑制活性. 其中, 2-{3-{{2-{[(1H-苯并咪唑-2-基)硫基]甲基}-3-甲基吡啶基-4-基}氧基}丙氧基}-1-(4-二苯甲基哌嗪-1-基)乙酮(7c)对上述三种癌细胞株的抑制活性最强, 其对人肺癌细胞株A549、人结直肠癌细胞株HCT116和人前列腺癌细胞株PC3的半数抑制浓度值分别是1.14、1.67和2.34 μmol/L. 初步构效关系和细胞机制研究显示, 化合物7c可诱导细胞发生G₀/G₁期阻滞. AnnexinV-PI双染的结果表明, 化合物7c可浓度依赖的诱导A549细胞凋亡. 上述结果提示, 具有2-[(吡啶-2-基甲基)硫基]-1H-苯并咪唑的化学结构骨架的化合物有望成为潜在的癌症化疗药物.

关键词: 苯并咪唑衍生物, 合成, 抗癌活性, 细胞凋亡

Benzimidazole is an important class of nitrogen-containing heterocyclic compounds, which has diverse biological activities. A series of novel 2-((pyridin-2-ylmethyl)thio)-1H-benzimidazole derivatives were reported and their antiproliferative activities against human lung cancer A549, human colorectal cancer HCT116 and human prostate cancer PC3 cell lines were evaluated with the MTT assay. Some target compounds demonstrated obvious antiproliferative activities against A549, HCT116 and PC3 cancer cell lines. Among them, 2-(3-((2-(((1H-benzimidazol-2-yl)thio)methyl)-3-methylpyridin-4-yl)oxy)propoxy)-1-(4-benzhydrylpiperazin-1-yl)ethanone (7c) showed the most potent antiproliferative activity with IC₅₀ values of 1.14 μmol/L for A549, 1.67 μmol/L for HCT116 and 2.34 μmol/L for PC3, respectively. Preliminary structure-activity relationships were summaried and preliminary cellular mechanism studies elucidated that compound 7c could arrest the cell cycle at G₀/G₁ phase. The flow cytometry analysis showed that compound 7c could dose-dependently induce A549 cells apoptosis. It is suggested that the 2-((pyridin-2-ylmethyl)thio)-1H-benzimidazole scaffold might be regarded as new scaffold structure for the development of potent cancer chemotherapeutic agents in the drug discovery process.

Key words: benzimidazole derivatives, synthesis, anticancer activity, apoptosis

引用此文

赵静, 金辄, 王润, 张新庚, 韩英妹, 胡春, 刘晓平, 张传明, 金丽萍. 2-[(吡啶-2-基甲基)硫基]-1H-苯并咪唑类化合物的设计、合成和抗癌活性研究[J]. 有机化学, 2022, 42(7): 2172-2183.

Jing Zhao, Zhe Jin, Run Wang, Xin'geng Zhang, Yingmei Han, Chun Hu, Xiaoping Liu, Chuanming Zhang, Liping Jin. Design, Synthesis and Anticancer Activity of 2-((Pyridin- 2-ylmethyl)thio)-1H-benzimidazole Derivatives[J]. Chinese Journal of Organic Chemistry, 2022, 42(7): 2172-2183.

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图/表 11

Figure 1. Chemical structures of PPIs

Figure 2. Chemical structures of some anticancer drugs

Figure 3. Spatial distance of the nitrogen atoms in pyridine ring and trifluoromethyl moiety of sorafenib (top) and a target compound (bottom)

Figure 4. Rational design of the target compounds based on molecular hybridization strategy

Scheme 1. Synthetic route of the target compounds 4a~4i Reagents and conditions: (a) CS2, Na2CO3, H2O, 30~90 ℃, 94.2%; (b) 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride, 2 mol/L NaOH (aq.), EtOH, r.t., 79.8%; (c) BBr3, CH2Cl2, –20 ℃, 83.6%; (d) ClCH2CONR1R2, K2CO3, KI, TBAB, acetone, reflux, 55.2%~71.3%

Scheme 2. Synthetic route of the target compounds 7a~7e and 11a~11d Reagents and conditions: (a) 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride, 2 mol/L NaOH (aq.), EtOH, r.t., 60.9%; (b) BBr3, CH2Cl2, –20 ℃, 69.5%; (c) ClCH2CONR3R4, K2CO3, KI, TBAB, acetone, reflux, 44.3%~52.8%; (d) (i) SOCl2, CHCl3, reflux; (ii) phthalimide potassium salt, DMF, 90 ℃, 45.7%; (iii) 80% N2H4•H2O, EtOH, reflux; (e) bis(trichloromethyl)carbonate, Et3N, r.t.; (f) 10a~10d, CH2Cl2, r.t., 47.1%~60.2%

Compd.	NR¹R²	IC₅₀/(μmol•L^–1)
Compd.	NR¹R²	A549	HCT116	PC3
4a		34.18±2.76	76.49±8.21	>100
4b		28.43±4.67	46.52±3.21	>100
4c		37.47±4.11	53.63±3.37	88.50±1.98
4d		44.09±0.17	74.14±1.28	>100
4e		40.69±12.04	37.08±2.82	>100
4f		20.87±1.23	27.90±0.79	72.47±0.46
4g		25.14±0.39	41.04±0.48	89.69±1.32
4h		19.45±0.91	34.63±0.82	79.83±2.58
4i		35.58±2.69	42.54±3.47	>100
Sorafinib		2.12±0.18	2.25±0.71	3.60±1.08

Table 1. Chemical structures and inhibitory activities of target compounds 4a~4i

Compd.	NR³R⁴	IC₅₀/(μmol•L^–1)
Compd.	NR³R⁴	A549	HCT116	PC3
7a		23.04±2.19	33.03±1.88	59.40±3.45
7b		5.04±2.07	9.82±3.81	48.37±4.23
7c		1.14±0.14	1.67±0.56	2.34±0.25
7d		5.59±0.90	12.55±1.04	45.70±3.43
7e		23.07±2.62	30.16±3.10	>100
sorafinib		2.12±0.18	2.25±0.71	3.60±1.08

Table 2. Chemical structures and inhibitory activities of target compounds 7a~7e

Compd.	R⁵	IC₅₀/(μmol•L^–1)
Compd.	R⁵	A549	HCT116	PC3
11a		13.71±2.39	11.90±1.47	>100
11b		9.36±0.76	10.22±1.61	>100
11c		13.29±2.31	15.93±1.11	62.93±1.35
11d		11.98±4.32	17.29±3.55	>100
sorafinib		2.12±0.18	2.25±0.71	3.60±1.08

Table 3. Chemical structures and inhibitory activities of target compounds 11a~11d

Figure 5. Compound 7c induced apoptosis of A549 cells (A) Apoptosis effect on A549 cell line induced by compound 7c for 48 h using Annexin V-FITC/PI double staining and flow-cytometry calculation. The lower left quadrant represents live cells, the lower right is for early apoptotic cells, upper right is for late apoptotic cells, and the upper left represents cells damaged during the procedure. (B) Quantitative analysis of apoptotic cells. The experiments were performed three times, and a representative experiment is shown.

Figure 6. Effects of compound 7c on A549 cell cycle progress for 24 h (A) Treatment of A549 cells with compound (7c) at different concentrations (1, 5, 10 μmol/L) for 24 h; (B) Quantitative analysis of cell cycle. The experiments were performed three times, and a representative experiment is shown

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2-[(吡啶-2-基甲基)硫基]-1H-苯并咪唑类化合物的设计、合成和抗癌活性研究

Design, Synthesis and Anticancer Activity of 2-((Pyridin- 2-ylmethyl)thio)-1H-benzimidazole Derivatives

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