Synthesis of (E)-N-(4-Styrene) Acrylamides for DNA Topoisomerase IIα Inhibitors and Antitumor Agents

doi:10.6023/cjoc202105008

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (1): 293-301.DOI: 10.6023/cjoc202105008 Previous Articles Next Articles

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(E)-N-(4-苯乙烯基)丙烯酰胺类DNA拓扑异构酶IIα抑制剂的合成及抗肿瘤活性研究

尹丽君, 李超群, 吴晓霞, 徐广森, 李志颖, 沈月毛^*()

山东大学药学院天然产物化学教育部重点实验室济南 250012

收稿日期:2021-05-06 修回日期:2021-06-06 发布日期:2021-06-29
通讯作者: 沈月毛
基金资助:
国家重点基础研究发展计划(973计划, No. 2010CB833802); 国家自然科学基金(81273384); 国家自然科学基金(90913024); 国家自然科学基金(91313303); 长江学者和创新团队发展计划(IRT_17R68); 国家杰出青年科学基金(30325044)

Synthesis of (E)-N-(4-Styrene) Acrylamides for DNA Topoisomerase IIα Inhibitors and Antitumor Agents

Lijun Yin, Chaoqun Li, Xiaoxia Wu, Guangsen Xu, Zhiying Li, Yuemao Shen()

Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012

Received:2021-05-06 Revised:2021-06-06 Published:2021-06-29
Contact: Yuemao Shen
Supported by:
National Basic Research Program of China (973 Program, No. 2010CB833802); National Natural Science Foundation of China(81273384); National Natural Science Foundation of China(90913024); National Natural Science Foundation of China(91313303); Program for Changjiang Scholars and Innovative Research Team in University(IRT_17R68); Distinguished Young Scholars Grant(30325044)

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Abstract

Human DNA topoisomerase IIα (Topo IIα) is one of the important targets of antitumor drugs. In this study, eighteen (E)-N-(4-styrene) acrylamide derivatives (A1~A9, B1~B9) were designed and synthesized through skeleton hopping of the lead compound CL-2 for the discovery of new high-efficient and low-toxic Topo IIα inhibitors. In vitro growth inhibition experiments of human triple negative breast cancer MDA-MB-231 cells and human acute myeloid leukemia KG1 cells were carried out for these eighteen compounds. Amongst, (E)-N-(4-((E)-3,5-dihydroxystyryl)phenyl)-3-(o-tolyl) acrylamide (B1) and (E)-N-(4-((E)-3,5-dihydroxystyryl)phenyl)-3-(4-nitrophenyl) acrylamide (B9) showed evident cytotoxicity against the KG1 cells with the IC₅₀ values of 0.43 and 0.5 μmol/L, respectively. (E)-N-(4-((E)-3,5-dihydroxyphenyl)phenyl)-3-(2- hydroxyphenyl) acrylamide (B4) showed stronger growth inhibitory effect (IC₅₀=0.82 μmol/L) against the MDA-MB-231 cells than that of the positive control VP16 (IC₅₀=6.62 μmol/L). (E)-N-(4-((E)-3,5-Dimethoxystyryl)phenyl)-3-(o-tolyl)- acrylamide (A1)、B1、(E)-N-(4-((E)-3,5-dimethoxystyryl)phenyl)-3-(2-methoxyphenyl)acrylamide (A4)、B4、(E)-N-(4-((E)- 3,5-dimethoxystyryl)phenyl)-3-(thiophen-3-yl)acrylamide (A9) and B9 inhibited Topo IIα-mediated DNA relaxation in vitro. These results provide a new direction for the discovery of new skeleton Topo IIα inhibitors.

Key words: topoisomerase IIα, design and synthesis, structure optimization, antitumor activity

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Lijun Yin, Chaoqun Li, Xiaoxia Wu, Guangsen Xu, Zhiying Li, Yuemao Shen. Synthesis of (E)-N-(4-Styrene) Acrylamides for DNA Topoisomerase IIα Inhibitors and Antitumor Agents[J]. Chinese Journal of Organic Chemistry, 2022, 42(1): 293-301.

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Fig. & Tab. 6

Figure 1. Structures of the representative Topo IIα inhibitors

Scheme 1. Design of (E)-N-(4-styrylphenyl)acrylamides

Scheme 2. Synthesis of compounds A1~A9 and B1~B9 Reagents and conditions: (i) triethyl phosphite, 140 oC, reflux, 4 h; (ii) 4-bromobenzaldehyde, NaOMe, DMF, r.t., overnight; (iii) thionyl chloride, DMF, DCM, r.t., 5 h; (iv) NH3·H2O, THF, 0 oC, 1 h; (v) CuI, N,N'-dimethyl-1,2-cyclohexanediamine, K2CO3, 1,4-dioxane, Ar, 110 oC, 24 h; (vi) BBr3, DCM, 0 oC, r.t., 5 h

Compd.	Ar	KG1/ (μmol•L^–1)	MDA-MB-231/ (μmol•L^–1)	Compd.	Ar	KG1/ (μmol•L^–1)	MDA-MB-231/ (μmol•L^–1)
A1	o-Tolyl	8.3	1.87	B2	m-Tolyl	3.18	7.61
A2	m-Tolyl	>10	>10	B3	p-Tolyl	7.92	6.52
A3	p-Tolyl	>10	>10	B4	2-Hydroxyphenyl	1.6	0.82
A4	2-Methoxyphenyl	>10	3.91	B5	3-Hydroxyphenyl	3.03	1.53
A5	3-Methoxyphenyl	>10	3.72	B6	4-Hydroxyphenyl	6.36	2.17
A6	4-Methoxyphenyl	>10	>10	B7	3-Nitrophenyl	2.58	3.49
A7	3-Nitrophenyl	>10	>10	B8	Thiophen-2-yl	1.59	4.02
A8	Thiophen-2-yl	>10	>10	B9	Thiophen-3-yl	0.5	1.88
A9	Thiophen-3-yl	>10	2.7	CL-2		1.35	2.90
B1	o-Tolyl	0.43	3.56	VP16		0.91	6.62

Table 1. Inhibitory activity of A1~A9 and B1~B9 against the growth of human breast cancer MDA-MB-231 cells and human acute myeloleukemia KG1 cells

Figure 2. Inhibitory activity of (E)-N-(4-styrylphenyl)acrylamides against DNA Topoisomerase IIα in vitro

Figure 3. Compound B9 docked into the binding site of Topo Iiα

References 28

[1]	The International Agency for Research on Cancer (IARC), 2020. Available from https://www.iarc.fr/fr/news-events/latest-global-cancer-data-cancer-burden-rises-to-19-3-million-new-cases-and-10- 0-million-cancer-deaths-in-2020/.
[2]	Infante Lara, L.; Sledge, A.; Laradji, A.; Okoro, C. O.; Osheroff, N. Bioorg. Med. Chem. Lett. 2017, 27, 586. doi: S0960-894X(16)31278-1 pmid: 27998679
[3]	Ortega, J. A.; Riccardi, L.; Minniti, E.; Borgogno, M.; Arencibia, J. M.; Greco, M. L.; Minarini, A.; Sissi, C.; De Vivo, M. J. Med. Chem. 2018, 61, 1375. doi: 10.1021/acs.jmedchem.7b01388
[4]	Wang, Y.; Sun, H.; Xiao, Z.; Zhang, G.; Zhang, D.; Bao, X.; Li, F.; Wu, S.; Gao, Y.; Wei, N. Cell Commun. Signal 2018, 16, 52. doi: 10.1186/s12964-018-0263-9
[5]	Heck, M. M.; Earnshaw, W. C. J. Cell Biol. 1986, 103, 2569. pmid: 3025219
[6]	Lyu, Y. L.; Lin, C. P.; Azarova, A. M.; Cai, L.; Wang, J. C.; Liu, L. F. Mol. Cell Biol. 2006, 26, 7929. doi: 10.1128/MCB.00617-06
[7]	Murty, M. S. R.; Penthala, R.; Polepalli, S.; Jain, N. Med. Chem. Res. 2016, 25, 627. doi: 10.1007/s00044-016-1514-1
[8]	Smith, T. P.; Windsor, I. W.; Forest, K. T.; Raines, R. T. J. Med. Chem. 2017, 60, 7820. doi: 10.1021/acs.jmedchem.7b00952
[9]	Xu, X. T.; Deng, X. Y.; Chen, J.; Liang, Q. M.; Zhang, K.; Li, D. L.; Wu, P. P.; Zheng, X.; Zhou, R. P.; Jiang, Z. Y.; Ma, A. J.; Chen, W. H.; Wang, S. H. Eur. J. Med. Chem. 2020, 189, 112013. doi: 10.1016/j.ejmech.2019.112013
[10]	Harper, D. E.; Welch, D. R. J. Antibiot. (Tokyo) 1992, 45, 1827. doi: 10.7164/antibiotics.45.1827
[11]	Sun, C. L.; Qu, P. P.; Li, F. Catal. Sci. Technol. 2014, 4, 988. doi: 10.1039/C3CY00934C
[12]	Yang, Y. H.; Li, G. H.; Song, Z. W.; Yang, X. L.; Liu, P. Lett. Org. Chem. 2010, 7, 533. doi: 10.2174/157017810793362316
[13]	Hollywood, F.; Suschitzky, H.; Hull, R. Synthesis-Stuttgart 1982, 662.
[14]	Cai, M. Z.; Zhao, H.; Hu, W. Y. Chin. J. Chem. 2005, 23, 443. doi: 10.1002/(ISSN)1614-7065
[15]	Maity, R.; Naskar, S.; Das, I. J. Org. Chem. 2018, 83, 2114. doi: 10.1021/acs.joc.7b03054
[16]	Naskar, D.; Roy, S. J. Chem. Soc., Perkin Trans. 1 1999, 2435.
[17]	Feng, Z. X.; Zheng, Y. D.; Zhao, L.; Zhang, Z. Y.; Sun, Y.; Qiao, K.; Xie, Y. J.; Wang, Y. S.; He, W. Mater. Sci. Eng. C 2019, 104, 109944. doi: 10.1016/j.msec.2019.109944
[18]	Mo, X. Y.; Wu, F. L.; Yu, B. L.; Wang, W. L.; Cai, X. L. Appl. Clay Sci. 2020, 193, 105664. doi: 10.1016/j.clay.2020.105664
[19]	Shou, J. Q.; Wang, M.; Cheng, X. L.; Wang, X. Y.; Zhang, L. F.; Liu, Y. C.; Fei, C. Z.; Wang, C. M.; Gu, F.; Xue, F. Q.; Li, J.; Zhang, K. Y. Arch. Pharm. Res. 2020, 43, 271. doi: 10.1007/s12272-020-01210-9
[20]	Chen, W. B.; Balakrishnan, K.; Kuang, Y. Y.; Han, Y. Y.; Fu, M.; Gandhi, V.; Peng, X. H. J. Med. Chem. 2014, 57, 4498. doi: 10.1021/jm401349g
[21]	Gootz, T. D.; Barrett, J. F.; Sutcliffe, J. A. Antimicrob. Agents Chemother. 1990, 34, 8. doi: 10.1128/AAC.34.1.8 pmid: 2158274
[22]	Marini, J. C.; Levene, S. D.; Crothers, D. M.; Englund, P. T. Proc. Natl. Acad. Sci. Biol. 1982, 79, 7664. doi: 10.1073/pnas.79.24.7664
[23]	Shen, Y.; Chen, W.; Li, Z. Y.; Shen, Y. M. Med. Chem. 2014, 10, 533. pmid: 24047216
[24]	Shen, Y.; Chen, W.; Zhao, B. B.; Hao, H. L.; Li, Z. Y.; Lu, C. H.; Shen, Y. M. Biochem. Biophys. Res. Commun. 2014, 453, 302. doi: 10.1016/j.bbrc.2014.09.042
[25]	Xiao, X.; Cushman, M. J. Am. Chem. Soc. 2005, 127, 9960. doi: 10.1021/ja042485n
[26]	Spitzer, R.; Jain, A. N. J. Comput. Aided Mol. Des. 2012, 26, 687. doi: 10.1007/s10822-011-9533-y
[27]	Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. J. Comput. Chem. 2009, 30, 2785. doi: 10.1002/jcc.v30:16
[28]	Sanner, M. F. J. Mol. Graphics Modell. 1999, 17, 57.

(E)-N-(4-苯乙烯基)丙烯酰胺类DNA拓扑异构酶IIα抑制剂的合成及抗肿瘤活性研究

Synthesis of (E)-N-(4-Styrene) Acrylamides for DNA Topoisomerase IIα Inhibitors and Antitumor Agents

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