含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究

doi:10.6023/cjoc202305025

有机化学 ›› 2024, Vol. 44 ›› Issue (1): 232-241.DOI: 10.6023/cjoc202305025 上一篇下一篇

研究论文

含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究

王博珍^a^,^b, 张婕^b, 粘春惠^b, 金茗茗^b, 孔苗苗^c, 李物兰^c, 何文斐^b^,^*(), 吴建章^a^,^b^,^*()

a 温州医科大学附属眼视光医院浙江温州 325027
b 温州医科大学药学院浙江温州 325035
c 温州医科大学附属第一医院浙江温州 325035

收稿日期:2023-05-18 修回日期:2023-08-16 发布日期:2023-09-15
作者简介:
^†共同第一作者.
基金资助:
浙江省自然科学基金(LGF20B020001); 浙江省自然科学基金(LGF21H160034); 国家自然科学基金(81903074)

Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides

Bozhen Wang^a^,^b, Jie Zhang^b, Chunhui Nian^b, Mingming Jin^b, Miaomiao Kong^c, Wulan Li^c, Wenfei He^b(), Jianzhang Wu^a^,^b()

a The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, Zhejiang 325027
b School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035
c The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035

Received:2023-05-18 Revised:2023-08-16 Published:2023-09-15
Contact: *E-mail: wjzwzmu@163.com; E-mail: wenfeihe@126.com
About author:
^†These authors contributed equally to this work.
Supported by:
Natural Science Foundation of Zhejiang Province(LGF20B020001); Natural Science Foundation of Zhejiang Province(LGF21H160034); National Natural Science Foundation of China(81903074)

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摘要/Abstract

为了寻找高效抗肿瘤活性化合物, 根据药物化学拼合原理, 在姜黄素骨架中引入酰胺键和3,4-二氯取代, 设计并合成了19个新型含有3,4-二氯苯基的酰胺类化合物. 用噻唑蓝比色法(MTT)检测化合物对AGS和BGC-823胃癌细胞的体外抗肿瘤活性. 结果表明, 部分化合物表现出良好的抑制胃癌细胞生长的活性, 其中(2E)-3-(3,4-二氯苯基)- 1-(2-{3-[4-(三氟甲基)苯基]丙酰基}乙氮基)丙-2-烯-1-酮(17)对AGS细胞的半数抑制浓度(IC₅₀)值为(1.94±0.94) μmol/L. 此外, 细胞集落形成、划痕、流式细胞术以及蛋白质印迹(Western blot)实验结果表明, 化合物17能明显抑制AGS细胞的生长和迁移, 阻滞细胞周期于G0/G1期, 并诱导促凋亡相关蛋白多聚腺苷二磷酸核糖聚合酶降解产物(Cleaved- PARP)及Bcl-2相关X蛋白(Bax)呈剂量依赖性上调, 诱导抗凋亡蛋白Bcl-2下调, 从而诱导细胞凋亡. 初步的机制研究显示, 化合物17可能通过抑制双特异性酪氨酸磷酸化调节激酶1A (DYRK1A)-蛋白激酶B (PKB, AKT)信号通路起到体外抗胃癌作用. 综上所述, 研究结果表明含有3,4-二氯苯基的酰胺类化合物可能是一类有药用研究前景的小分子化合物, 化合物17有望成为一种抗肿瘤候选化合物.

关键词: 姜黄素类似物, 3,4-二氯苯基, 酰胺键, 合成, 抗肿瘤活性

In order to find efficient antitumor compounds, 19 novel 3,4-dichlorophenyl amides were designed and synthesized by introducing amide bonds and 3,4-dichloro substitution into the curcumin skeleton according to the principles of medicinal chemistry combination. The in vitro antitumor activity of the compounds against AGS and BGC-823 gastric cancer cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results showed that some compounds displayed potential inhibitory activity. Notably, (2E)-3-(3,4-dichlorophenyl)-1-(2-(3-(4-(trifluoromethyl)phenyl)propio- nyl)ethylazo)propan-2-en-1-one (17) showed potent growth inhibition on AGS with a half maximal inhibitory concentration (IC₅₀) value of (1.94±0.94) μmol/L. Besides, the results of cell colony formation, wound healing, flow cytometry and western blot showed that compound 17 significantly inhibited the growth and migration of AGS cells, arrested the cell cycle in G0/G1 phase, and induced a dose-dependent up-regulation of the pro-apoptotic proteins such as cleaved poly ADP-ribose polymerase (Cleaved-PARP) and Bcl2-associated X protein (Bax), and a down-regulation of the anti-apoptotic protein Bcl-2, thus inducing cell apoptosis. Preliminary mechanistic studies suggested that compound 17 may exert its anti-gastric cancer effects in vitro by inhibiting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A)-protein kinase B (PKB, AKT) signaling pathway. In conclusion, this study indicates that amide compounds containing 3,4-dichlorophenyl may be a class of small molecule compounds with promising prospects for medicinal research, and compound 17 is expected to be an antitumor candi-date.

Key words: curcumin analog, 3,4-dichlorophenyl, amide bond, synthesis, antitumor activity

引用此文

王博珍, 张婕, 粘春惠, 金茗茗, 孔苗苗, 李物兰, 何文斐, 吴建章. 含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究[J]. 有机化学, 2024, 44(1): 232-241.

Bozhen Wang, Jie Zhang, Chunhui Nian, Mingming Jin, Miaomiao Kong, Wulan Li, Wenfei He, Jianzhang Wu. Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides[J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 232-241.

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图/表 8

图1. (A)含有3,4-二氯苯基片段的抗肿瘤化合物和(B)含3,4-二氯的酰胺类化合物的设计

Figure 1. (A) Compounds containing 3,4-dichlorobenzene base fragment with antitumor activity and (B) design of amide compounds containing 3,4-dichloride

图式1. 化合物1~17的合成路线

Scheme 1. Synthetic route of compounds 1~17

图式2. 化合物18和19的合成路线

Scheme 2. Synthetic route of compounds 18 and 19

Compd.	X	Z	Y	R	Growth inhibition/%
Compd.	X	Z	Y	R	AGS	BGC-823
1	CH=CH	CH=CH	—	2-OCH₃	49.43±2.43	NA
2	CH=CH	CH=CH	—	2-Br	42.28±0.12	NA
3	CH=CH	CH=CH	—	2-Cl	32.52±1.39	NA
4	CH=CH	CH=CH	—	2-CF₃	46.59±2.28	17.83±0.40
5	CH=CH	CH=CH	—	2-NO₂	33.56±0.19	NA
6	CH=CH	CH=CH	—	2,3-(OCH₃)₂	38.96±1.58	8.98±0.52
7	CH=CH	CH=CH	—	2,4-(OCH₃)₂	29.87±1.86	6.90±0.77
8	CH=CH	CH=CH	—	2,4-Me₂	34.41±0.69	NA
9	CH=CH	CH=CH	—	3,4-Me₂	44.41±2.56	NA
10	CH=CH	CH=CH	—	4-N(Me)₂	48.77±2.12	NA
11	CH=CH	CH=CH	—		48.78±2.36	NA
12	CH=CH	CH=CH	—		43.46±1.23	NA
13	CH₂	CH₂		3,4-Cl₂	NA	6.14±1.77
14	CH=CH	CH=CH		3,4-Cl₂	41.10±1.09	2.78±1.76
15	—	—	(CH₂)₄	3,4-Cl₂	44.65±1.63	26.32±1.89
16	CH=CH	(CH₂)₂	—	3,4-Cl₂	76.75±2.10	3.87±1.94
17	CH=CH	(CH₂)₂	—	4-CF₃	83.95±0.35	45.66±0.81
18					4.95±0.64	6.67±2.51
19					37.45±1.48	20.05±1.91
1f					64.77±0.01	36.16±0.04
Curcumin^b					70.43±8.89	38.52±6.64

表1. 浓度为10 μmol/L时化合物1~19对AGS和BGC-823胃癌细胞的体外生长抑制率(%)a

Table 1. In vitro growth inhibitory activity (%) of compounds 1~19 on gastric cancer cells AGS and BGC-823 at concentration of 10 μmol/L

图2. 化合物17对AGS生长及迁移的影响

Figure 2. Effects of compound 17 on the growth and migration of AGS cells (A) Representative images of AGS cell colonies treated with various concentrations of compound 17; (B) effect of compound 17 on migration of AGS gastric cancer cells. **p<0.01, ****p<0.0001 vs DMSO.

图3. 化合物17对AGS细胞周期的影响

Figure 3. Effects of compound 17 on the cell cycle of AGS cells

图4. 化合物17对AGS胃癌细胞凋亡的影响

Figure 4. Effects of compound 17 on apoptosis of AGS gastric cancer cells (A) Apoptosis rate was detected by flow cytometry; (B) the expressions of apoptosis-related proteins cleaved-PARP, Bcl-2 and Bax were detected by Western blot. *p<0.05, **p<0.01 vs DMSO.

图5. 化合物17对胃癌细胞DYRK1A-AKT信号通路的影响

Figure 5. Effects of compound 17 on DYRK1A-AKT signaling pathway in gastric cancer cells *p<0.05, **p<0.01 vs DMSO.

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含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides

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