Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives

doi:10.1016/j.ejmech.2016.02.070

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	Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives
	Song, ZL; Wang, MJ; Li, LL; Wu, D; Wang, YH; Yan, LT; Morris-Natschke, SL; Liu, YQ; Zhao, YL; Wang, CY
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2016-06-10
卷号	115 页码:109-120
关键词	Camptothecin Cytotoxic activity Molecular docking Sulfonylamidine Synthesis
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2016.02.070
文献子类	Article
英文摘要	In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the anti proliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from I and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and pi-pi stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity. (C) 2016 Elsevier Masson SAS. All rights reserved.
学科主题	Pharmacology & Pharmacy
出版地	PARIS
资助项目	国家自然科学基金项目 ; 中央高校基本科研业务费专项资金 ; 美国国立卫生研究院项目
项目编号	National Natural Science Foundation of China [30800720, 31371975] ; Xinjiang Production & Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin [BYRB1306] ; Fundamental Research Funds for the Central Universities [lzujbky-2014-k19] ; NIH grant from the National Cancer Institute [CA177584] ; Health and Welfare Surcharge of Tobacco Products, China Medical University Hospital Cancer Research Center of Excellence (Taiwan) [MOHW103-TD-B-111-03]
语种	英语
WOS记录号	WOS:000375360800010
资助机构	NSFC ; LZU ; NIH
内容类型	期刊论文
源URL	[http://ir.lzu.edu.cn/handle/262010/179589]
专题	药学院_期刊论文
通讯作者	Liu, YQ; Liu, HX (reprint author), Lanzhou Univ, Sch Pharm, Lanzhou 730000, Peoples R China.; Lee, KH (reprint author), Univ N Carolina, Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA.; Lee, KH (reprint author), China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung, Taiwan.
推荐引用方式 GB/T 7714	Song, ZL,Wang, MJ,Li, LL,et al. Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2016,115:109-120.
APA	Song, ZL.,Wang, MJ.,Li, LL.,Wu, D.,Wang, YH.,...&Lee, KH .(2016).Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,115,109-120.
MLA	Song, ZL,et al."Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 115(2016):109-120.