Antitumor and Topoisomerase Ⅱα Inhibitory Activities of 3-Aryl-7-hydroxyquinolines

doi:10.6023/cjoc201905013

Chinese Journal of Organic Chemistry ›› 2019, Vol. 39 ›› Issue (11): 3230-3236.DOI: 10.6023/cjoc201905013 Previous Articles Next Articles

3-芳基-7-羟基喹啉类拓扑异构酶Ⅱα抑制剂的合成及抗肿瘤活性研究

胡园^a, 李震宇^b, 丁艳娇^b, 李志颖^a, 刘志勇^a, 沈月毛^a*()

^a山东大学药学院天然产物化学教育部重点实验室济南 250012
^b 山东大学附属省立医院药剂科济南 250021

收稿日期:2019-05-08 发布日期:2019-06-24
通讯作者: 沈月毛 E-mail:yshen@sdu.edu.cn
基金资助:
国家重点基础研究发展计划(973计划);国家重点基础研究发展计划(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);国家杰出青年科学基金(30325044);长江学者与创新团队发展计划(IRT_17R68)

Antitumor and Topoisomerase Ⅱα Inhibitory Activities of 3-Aryl-7-hydroxyquinolines

Hu Yuan^a, Li Zhenyu^b, Ding Yanjiao^b, Li Zhiying^a, Liu Zhiyong^a, Shen Yuemao^a*()

^a Key Laboratory of Chemical Biology(Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012
^b Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021

Received:2019-05-08 Published:2019-06-24
Contact: Shen Yuemao E-mail:yshen@sdu.edu.cn
Supported by:
the National Basic Research Program of China(973计划);the National Basic Research Program of China(2010CB833802);the National Natural Science Foundation of China(81273384);the National Natural Science Foundation of China(90913024);the National Natural Science Foundation of China(91313303);the National Science Foundation for Distinguished Young Scholars of China(30325044);the Program for Changjiang Scholars and Innovative Research Team in University(IRT_17R68)

1. .pdf(1469KB)

Abstract

Human deoxyribonucleic acid (DNA) topoisomerase Ⅱα (Topo Ⅱα) is one of the important therapeutic targets for the treatment of cancers. To further discover Topo Ⅱα inhibitors with high efficiency and low toxicity, twenty-one 3-aryl-7-hydroxyquinolines were designed and synthesized by scaffold hopping of the lead compound 4-(6-hydroxynaph-thalen-2-yl)benzene-1, 2-diol (CS1). These compounds were evaluated for their inhibitory activity against Topo Ⅱα activity in DNA relaxation assays, and evaluated for the antitumor activity in in vitro growth inhibition assays against human triple negative breast cancer MDA-MB-231 cells and human cervical cancer HeLa cells. DNA relaxation assays showed that most compounds have inhibitory activity against Topo Ⅱα. In vitro growth inhibition assays showed that 3-(2, 4-dimethoxyphenyl)-7-hydroxyquinoline (4j) has obvious cytotoxicity against HeLa cells (IC₅₀=0.8 μmol·L^-1), and 3-(4-hydroxyphenyl)-7-hydroxyquinoline (4e) has evident cytotoxicity against both MDA-MB-231 (IC₅₀=1.1 μmol·L^-1) and HeLa cell lines (IC₅₀=4.2 μmol·L^-1). These results provide insight into the development of novel quinoline topoisomerase Ⅱα inhibitors.

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

Cite this article

Hu Yuan, Li Zhenyu, Ding Yanjiao, Li Zhiying, Liu Zhiyong, Shen Yuemao. Antitumor and Topoisomerase Ⅱα Inhibitory Activities of 3-Aryl-7-hydroxyquinolines[J]. Chinese Journal of Organic Chemistry, 2019, 39(11): 3230-3236.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 4

Figure 1. Structures of representative Topo Ⅱ inhibitors

Scheme 1. Synthesis of compounds 4a~4uReagents and conditions: (ⅰ) 2-bromomalonaldehyde, ethanol, r.t., overnight; ethanoic acid, 100 ℃, reflux, 10 d; (ⅱ) methanesulfonic acid, methionine, 130 ℃, 23 h; (ⅲ) substituted-aryl boronic acid/borate, potassium acetate, PdCl2(dppf), dioxane, 90 ℃, overnight

Figure 2. Inhibitory activity of 3-aryl-7-hydroxyquinolines against DNA topoisomerase Ⅱα in vitro

Compd.	MDA-MB-231	HeLa
4e	1.1	4.2
4j	7.3	0.8
4n	10.6	25.3
4p	9.0	13.7
4q	11.4	17.1
4r	20.5	15.9
4s	16.7	＞50
4t	＞50	5.2
4u	18.4	＞50
CS1	3.8	2.5
VP16	2.7	2.1

Table 1. Inhibitory activity of the anti-Topo Ⅱα compounds against the human triple negative breast cancer MDA-MB-231 cells and human cervical cancer HeLa cells

References 23

[1]	World Health Organization (WHO), WHO cancer 2018, Available from: , 2018.
[2]	Costa R. Shah A. N. Santa-Maria C. A. Cruz M. R. Mahalingam D. Carneiro B. A. Chae Y. K. Cristofanilli M. Gradishar W. J. Giles F. J. Cancer Treat Rev. 2017 53 111. doi: 10.1016/j.ctrv.2016.12.010
[3]	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
[4]	Infante Lara L. Sledge A. Laradji A. Okoro C. O. Osheroff N. Bioorg. Med. Chem. Lett. 2017 27 586. doi: 10.1016/j.bmcl.2016.12.011
[5]	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
[6]	Shapiro A. B. Austin C. A. Anal. Biochem. 2014 448 23. doi: 10.1016/j.ab.2013.11.029
[7]	Guan M. Qiu J. Lu C. Zhao B. Shen Y. Chin. J. Org. Chem. 2018 38 3039. doi: 10.6023/cjoc201805035
	关梦佳邱进鲁春华赵保兵沈月毛有机化学 2018 38 3039. doi: 10.6023/cjoc201805035
[8]	Park S. Hong E. Kwak S. Y. Jun K. Y. Lee E. S. Kwon Y. Na Y. Eur. J. Med. Chem. 2016 123 211. doi: 10.1016/j.ejmech.2016.07.046
[9]	Wu X. Yalowich J. C. Hasinoff B. B. J. Inorg. Biochem. 2011 105 833. doi: 10.1016/j.jinorgbio.2011.02.007
[10]	Coustry F. Maity S. N. de Crombrugghe B. J. Biol. Chem. 1995 270 468. doi: 10.1074/jbc.270.1.468
[11]	McClendon A. K. Osheroff N. Mutat. Res. 2007 623 83. doi: 10.1016/j.mrfmmm.2007.06.009
[12]	Chen W. Shen Y. Li Z. Zhang M. Lu C. Shen Y. Eur. J. Med. Chem. 2014 86 782. doi: 10.1016/j.ejmech.2014.08.073
[13]	Hao H. Chen W. Zhu J. Lu C. Shen Y. Eur. J. Med. Chem. 2015 102 277. doi: 10.1016/j.ejmech.2015.07.048
[14]	Tseng C. H. Chen Y. R. Tzeng C. C. Liu W. Chou C. K. Chiu C. C. Chen Y. L. Eur. J. Med. Chem. 2016 108 258. doi: 10.1016/j.ejmech.2015.11.031
[15]	Khadka D. B. Woo H. Yang S. H. Zhao C. Jin Y. Le T. N. Kwon Y. Cho W.-J. Eur. J. Med. Chem. 2015 92 583. doi: 10.1016/j.ejmech.2015.01.016
[16]	Zhao H. Drug Discovery Today 2007 12 149. doi: 10.1016/j.drudis.2006.12.003
[17]	Shen Y. Chen W. Zhao B. Hao H. Li Z. Lu C. Shen Y. Biochem. Biophys. Res. Commun. 2014 453 302. doi: 10.1016/j.bbrc.2014.09.042
[18]	Li Z. Ding Y. Bu H. Shen Y. Chin. J. Org. Chem. 2018 38 3204. doi: 10.6023/cjoc201806015
	李志颖丁艳娇卜华港沈月毛有机化学 2018 38 3204. doi: 10.6023/cjoc201806015
[19]	Frotscher M. Ziegler E. Marchais-Oberwinkler S. Kruchten P. Neugebauer A. Fetzer L. Scherer C. Mueller-Vieira U. Messinger J. Thole H. Hartmann R. W. J. Med. Chem. 2008 51 2158. doi: 10.1021/jm701447v
[20]	Krishnan R. Seshadri S. Dyes Pigm. 1986 7 69. doi: 10.1016/0143-7208(86)87007-3
[21]	Xiao X. Cushman M. J. Am. Chem. Soc. 2005 127 9960. doi: 10.1021/ja042485n
[22]	Huang Y. Wang J. Li G. Zheng Z. Su W. FEMS Immunol. Med. Microbiol. 2001 31 163. doi: 10.1111/j.1574-695X.2001.tb00513.x
[23]	Carmichael J. DeGraff W. G. Gazdar A. F. Minna J. D. Mitchell J. B. Cancer Res. 1987 47 943.

3-芳基-7-羟基喹啉类拓扑异构酶Ⅱα抑制剂的合成及抗肿瘤活性研究

Antitumor and Topoisomerase Ⅱα Inhibitory Activities of 3-Aryl-7-hydroxyquinolines

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 4

References 23

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	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.
[2]	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.
[3]	Panxing Pang, Rong Ning, Chuang Zhu, Wenjie Huang, Xianli Ma, Caina Jiang, Fangyao Li, Xiaoqun Zhou. Synthesis and in Vitro Antitumor Activity of Matrine Semicarbazide Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2126-2135.
[4]	Kanghui Duan, Junlong Tang, Wanqing Wu. Recent Advances in the Synthesis of Fused Heterocyclic Compounds and Their Antitumor Activities [J]. Chinese Journal of Organic Chemistry, 2023, 43(3): 826-854.
[5]	Weiqin Liu, Lihui Shao, Chengpeng Li, Yayu Zou, Haitao Long, Yan Li, Qiangsheng Ge, Zhenchao Wang, Guiping Ouyang. Synthesis and Antitumor Activity of 3-Hydrazone Quinazolinone Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(1): 214-222.
[6]	Zhaohua Chen, Xiying Cao, Sihong Chen, Shiwei Yu, Yanlan Lin, Shuting Lin, Zhaoyang Wang. Design, Synthesis and Application of Trisubstituted Olefinic Aggregation-Induced Emission Molecules [J]. Chinese Journal of Organic Chemistry, 2022, 42(8): 2355-2363.
[7]	Dongyan Hu, Guangtian Han, Xi'an Li, Huazhong Ren, Lirong Yue, Li Guo, Jiafu Feng. Synthesis and Evaluation in vitro of Novel Harmine Derivatives as Anticancer Activity Agents [J]. Chinese Journal of Organic Chemistry, 2022, 42(6): 1863-1871.
[8]	Lu Xue, Lihua Zhang, Chengyu Zhang, Xin Zhao, Weifan Dang, Zhaoxin Wang, Chunhua Wang, Tongchuan Suo, Xiaohui Yan. Discovery of Tiancimycin Congeners from Streptomyces sp. CB03234-S [J]. Chinese Journal of Organic Chemistry, 2022, 42(4): 1241-1247.
[9]	Honglin Dai, Xiaojie Si, Lingling Chi, Hao Wang, Chao Gao, Zhengjie Wang, Limin Liu, Jiajie Ma, Fuqiang Yu, Hongmin Liu, Yu Ke, Qiurong Zhang. Synthesis and Antitumor Activity Evaluation of 2,4,6-Trisubstituted Quinazoline Derivatives Containing Thiazole Structure [J]. Chinese Journal of Organic Chemistry, 2022, 42(11): 3853-3862.
[10]	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.
[11]	Zhengjie Wang, Honglin Dai, Xiaojie Si, Chao Gao, Limin Liu, Luye Zhang, Yang Zhang, Yadan Song, Peirong Zhao, Jiaxin Zheng, Yu Ke, Hongmin Liu, Qiurong Zhang. Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl [J]. Chinese Journal of Organic Chemistry, 2022, 42(1): 249-256.
[12]	Jiaoli Ma, Penghu Guo, Jing Li, Xincheng Liao, Huicheng Cheng. Synthesis and Antitumor Activity of Amide Derivatives Containing 1,3,4-Thiadiazole and Pyrazole Moieties [J]. Chinese Journal of Organic Chemistry, 2021, 41(8): 3214-3222.
[13]	Ningbo Li, Li Xu, Rong Ma, Qi Fan, Bo Li, Jie Qiao, Rui Guo, Xinhua Xu. Synthesis and Antitumor Activities of Novel Organic Sulfur (Selenium) Tegafur Derivatives [J]. Chinese Journal of Organic Chemistry, 2021, 41(7): 2723-2734.
[14]	Yinghao Liu, Fangxia Lin, Yinfeng Tan, Jingyu Yang, Bin Zhang, Xueming Zhou, Xinming Song. Three New Phenanthraquinones from the Root of Dendrobium nobile [J]. Chinese Journal of Organic Chemistry, 2021, 41(5): 2112-2115.
[15]	Yuxun Zhao, Yunyun Wang, Chenglong Zhang, Xu Xu, Shifa Wang. Synthesis of Novel Camphor Sulfamoxime Ether Derivatives and Its Application in Antitumor Activity [J]. Chinese Journal of Organic Chemistry, 2021, 41(3): 1224-1233.