A New Class of Naphthalimide-Based Antitumor Agents That Inhibit Topoisomerase II and Induce Lysosomal Membrane Permeabilization and Apoptosis

doi:10.1021/jm100025u

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	A New Class of Naphthalimide-Based Antitumor Agents That Inhibit Topoisomerase II and Induce Lysosomal Membrane Permeabilization and Apoptosis
	Chen, Zhuo 2; Liang, Xin 2; Zhang, Huanying 2; Xie, Hua1,2 ; Liu, Jianwen 2; Xu, Yufang 2; Zhu, Weiping 2; Wang, Yi 1; Wang, Xin2 ; Tan, Shaoying 2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2010-03-25
卷号	53 期号:6 页码:2589-2600
ISSN号	0022-2623
DOI	10.1021/jm100025u
文献子类	Article
英文摘要	Based on the advantages of multitarget drugs for cancer treatment, a new class of naphthalimides was designed, synthesized, and proved to inhibit topoisomerase II (topo II), induced lysosomal membrane permeabilization (LMP), and ultimately caused apoptosis and cell death. The majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC(50) values ranging from 2 to 10 mu M and are more active than amonafide, a naphthahmide that was in phase III clinical trials. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topo II inhibitors. Furthermore, compounds 7b-d were found to notably induce LMP and exhibited better antiproliferative activity compared with their single-target analogues. All of the newly synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.
资助项目	Key New Drug Creation and Manufacturing Program[2009ZX09103-102] ; National High Technology Research and Development Program of China[2006AA10A201] ; China 111 Project[1307023] ; Shanghai Leading Academic Discipline Project[B507]
WOS关键词	BASIC BIOLOGICAL PHENOMENON ; DESIGNED MULTIPLE LIGANDS ; WIDE-RANGING IMPLICATIONS ; DRUG DISCOVERY PARADIGM ; TUMOR-CELL DEATH ; CANCER-THERAPY ; LYSOSOMOTROPIC DETERGENT ; ANTICANCER AGENTS ; CYTOCHROME-C ; DNA
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000275711000025
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278940]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Xu, Yufang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;
推荐引用方式 GB/T 7714	Chen, Zhuo,Liang, Xin,Zhang, Huanying,et al. A New Class of Naphthalimide-Based Antitumor Agents That Inhibit Topoisomerase II and Induce Lysosomal Membrane Permeabilization and Apoptosis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2010,53(6):2589-2600.
APA	Chen, Zhuo.,Liang, Xin.,Zhang, Huanying.,Xie, Hua.,Liu, Jianwen.,...&Qian, Xuhong.(2010).A New Class of Naphthalimide-Based Antitumor Agents That Inhibit Topoisomerase II and Induce Lysosomal Membrane Permeabilization and Apoptosis.JOURNAL OF MEDICINAL CHEMISTRY,53(6),2589-2600.
MLA	Chen, Zhuo,et al."A New Class of Naphthalimide-Based Antitumor Agents That Inhibit Topoisomerase II and Induce Lysosomal Membrane Permeabilization and Apoptosis".JOURNAL OF MEDICINAL CHEMISTRY 53.6(2010):2589-2600.