Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides

doi:10.6023/cjoc202305025

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (1): 232-241.DOI: 10.6023/cjoc202305025 Previous Articles Next Articles

ARTICLES

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)

1. .pdf(2473KB)

Abstract

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

Cite this article

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.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 8

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

Scheme 1. Synthetic route of compounds 1~17

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

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

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.

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

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.

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

References 23

[1]	Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Ca-Cancer J. Clin. 2021, 71, 209. doi: 10.3322/caac.v71.3
[2]	Tsai, C. H.; Lin, Y. H.; Li, Y. S.; Ho, T. L.; Hoai Thuong, L. H.; Liu, Y. H. Int. J. Mol. Sci. 2021, 22, 9257. doi: 10.3390/ijms22179257
[3]	Margiotta, E.; van der Lubbe, S. C. C.; de Azevedo Santos, L.; Paragi, G.; Moro, S.; Bickelhaupt, F. M.; Fonseca Guerra, C. J. Chem. Inf. Model. 2020, 60, 1317. doi: 10.1021/acs.jcim.9b00946
[4]	Wilcken, R.; Zimmermann, M. O.; Lange, A.; Joerger, A. C.; Boeckler, F. M. J. Med. Chem. 2013, 56, 1363. doi: 10.1021/jm3012068
[5]	Fang, W. Y.; Ravindar, L.; Rakesh, K. P.; Manukumar, H. M.; Shantharam, C. S.; Alharbi, N. S.; Qin, H. L. Eur. J. Med. Chem. 2019, 173, 117. doi: 10.1016/j.ejmech.2019.03.063
[6]	Koksal, M.; Yarim, M.; Erdal, A.; Bozkurt, A. Drug Res. (Stuttgart, Ger.) 2014, 64, 66. doi: 10.1055/s-00023610
[7]	Koksal, M.; Bilge, S. S.; Bozkurt, A.; Sahin, Z. S.; Isik, S.; Erol, D. D. Arzneimittelforschung 2008, 58, 510. doi: 10.1055/s-0031-1296550
[8]	Scozzafava, A.; Mastrolorenzo, A.; Supuran, C. T. J. Enzyme Inhib. 2001, 16, 425.
[9]	Onda, K.; Shiraki, R.; Yonetoku, Y.; Momose, K.; Katayama, N.; Orita, M.; Yamaguchi, T.; Ohta, M.; Tsukamoto, S. Bioorg. Med. Chem. 2008, 16, 8627. doi: 10.1016/j.bmc.2008.08.010
[10]	Budke, B.; Kalin, J. H.; Pawlowski, M.; Zelivianskaia, A. S.; Wu, M.; Kozikowski, A. P.; Connell, P. P. J. Med. Chem. 2013, 56, 254. doi: 10.1021/jm301565b
[11]	Baker, J. R.; Gilbert, J.; Paula, S.; Zhu, X.; Sakoff, J. A.; Mc-Clus- key, A. ChemMedChem 2018, 13, 1447. doi: 10.1002/cmdc.v13.14
[12]	Szafrański, K.; Sławiński, J. Molecules 2015, 20, 12029. doi: 10.3390/molecules200712029
[13]	Peterson, Y. K.; Kelly, P.; Weinbaum, C. A., Casey, P. J. J. Biol. Chem. 2006, 281, 12445. doi: 10.1074/jbc.M600168200
[14]	Kumari, S.; Carmona, A. V.; Tiwari, A. K.; Trippier, P. C. J. Med. Chem. 2020, 63, 12290. doi: 10.1021/acs.jmedchem.0c00530
[15]	Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471. doi: 10.1038/nature10702
[16]	Tang, J.-J. M.S. Thesis, Hunan University, Changsha, 2017 (in Chinese).
	(唐晶晶, 硕士论文, 湖南大学, 长沙, 2017.)
[17]	Strharsky, T.; Pindjakova, D.; Kos, J.; Vrablova, L.; Michnova, H.; Hosek, J.; Strakova, N.; Lelakova, V.; Leva, L.; Kavanova, L.; Oravec, M.; Cizek, A.; Jampilek, J. Int. J. Mol. Sci. 2022, 23, 3159. doi: 10.3390/ijms23063159
[18]	Yu, P.; Hu, J.; Zhou, T. Y.; Wang, P.; Xu, Y. H. J. Chem. Res. 2011, 35, 703. doi: 10.3184/174751911X13230201951890
[19]	Esterhuysen, C.; Heßelmann, A.; Clark, T. ChemPhysChem 2017, 18, 772. doi: 10.1002/cphc.v18.7
[20]	Abula, A.; Xu, Z.; Zhu, Z.; Peng, C.; Chen, Z.; Zhu, W.; Aisa, H. A. J. Chem. Inf. Model. 2020, 60, 6242. doi: 10.1021/acs.jcim.0c00898
[21]	He, X.-H.; Li, H.-P.; Zhao, Q.; Peng, C.; Huang, W. Chin. Arch. Tradit. Chin. Med. 2022, 40, 175 (in Chinese).
	(何享鸿, 李和平, 赵倩, 彭成, 黄维, 中华中医药学刊, 2022, 40, 175.)
[22]	Rammohan, M.; Harris, E.; Bhansali, R. S.; Zhao, E.; Li, L. S.; Crispino, J. D. Oncogene 2022, 41, 2003. doi: 10.1038/s41388-022-02245-6
[23]	Chen, Z. Y.; Li, J.; Zhu, S. D.; Li, Z. D.; Yu, J. L.; Wu, J.; Zhang, C.; Zeng, L. H. Exp. Ther. Med. 2022, 23, 209. doi: 10.3892/etm

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

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 8

References 23

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Penghui Li, Qingyang Xie, Fuxian Wan, Yuanhong Zhang, Lin Jiang. Synthesis and Fungicidal Activity of Novel Substituted Pyrimidine-5-carboxamides Bearing Cyclopropyl Moiety [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 650-656.
[2]	Fakai Zou, Nengzhong Wang, Hui Yao, Hui Wang, Mingguo Liu, Nianyu Huang. Regio- and Stereo-selective Synthesis of 1β-/3R-Aryl Thiosugar [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 593-604.
[3]	Luyao Li, Zhongwen He, Zhenguo Zhang, Zhenhua Jia, Teck-Peng Loh. Application of Triaryl Carbenium in Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 421-437.
[4]	Qinggang Mei, Qinghan Li. Recent Progress of Visible Light-Induced the Synthesis of C(3) (Hetero)arylthio Indole Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 398-408.
[5]	Shihang Yu, Jiawei Liu, Biyu An, Qinghua Bian, Min Wang, Jiangchun Zhong. Asymmetric Synthesis of the Contact Sex Pheromone of Neoclytus acuminatus acuminatus (Fabricius) [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 301-308.
[6]	Weiqing Yang, Yanbing Ge, Yuanyuan Chen, Ping Liu, Haiyan Fu, Menglin Ma. Design and Synthesis of Fluorescent 1,8-Napthalimide Derivatives and Their Identification of Cysteine [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 180-194.
[7]	Qianfan Zhao, Yongzheng Chen, Shiming Zhang. Application and Mechanism Study of Carbon-Based Metal-Free Catalysts in Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 137-147.
[8]	Shan Chen, Zhilin Chen, Qiong Hu, Yanshuang Meng, Yue Huang, Pingfang Tao, Liru Lu, Guobao Huang. Recognition of Bis-thiourea Tweezers to Neutral Molecules in Non-Polar Solvent [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 277-281.
[9]	Huakun Wang, Xiaolong Ren, Yining Xuan. Study of the Halide Salt Catalyzed [3＋2] Cycloaddition of α,β-Epoxy Carboxylate with Isocyanate [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 251-258.
[10]	Yukun Jin, Baoyi Ren, Fushun Liang. Visible Light-Mediated Selective C—F Bond Cleavage of Trifluoromethyl Groups and Its Application in Synthesizing gem-Difluoro-Containing Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 85-110.
[11]	Cuiyun Ma, Hailan Luo, Fuhua Zhang, Dan Guo, Shuxing Chen, Fei Wang. Green Biosynthesis, Photophysical Properties and Application of 3-Pyrrolyl BODIPY [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 216-223.
[12]	Ruixia Cao, Yuping Jia. Synthesis and Biological Activity of Novel Pyrrolo[2,3-d]pyrimidine Derivatives Containing Coumarin [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3304-3311.
[13]	Huanqing Li, Zhaohua Chen, Zujia Chen, Qiwen Qiu, Youcai Zhang, Sihong Chen, Zhaoyang Wang. Research Progress in Mercury Ion Fluorescence Probes Based on Organic Small Molecules [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3067-3077.
[14]	Ran Zhou, Chunmei Yuan, Tao Zhang, Piao Mao, Yi Liu, Kaini Meng, Hui Xin, Wei Xue. Design, Synthesis and Bioactivity of Chalcone Derivative Containing Quinazolinone [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3196-3209.
[15]	Yang Li, Jinding Yuan, Di Zhao. Deep Eutectic Solvent of 1,3-Dimethylurea/L-(+)-Tartaric Acid for the Green Synthesis of (E)-2-Styrylquinoline-3-carboxylic Acid Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3268-3276.