文献类型：期刊文献

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

作者：Chen, Zhuo[1];Liang, Xin[1];Zhang, Huanying[1];Xie, Hua[1,2];Liu, Jianwen[1];Xu, Yufang[1];Zhu, Weiping[1];Wang, Yi[2];Wang, Xin[1];Tan, Shaoying[1];Kuang, Dong[1];Qian, Xuhong[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2010

卷号：53

期号：6

起止页码：2589

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000275711000025)】；

基金：This work was financially supported by the Key New Drug Creation and Manufacturing Program (2009ZX09103-102), the National High Technology Research and Development Program of China (863 Program 2006AA10A201), the China 111 Project (Grant 1307023), and the Shanghai Leading Academic Discipline Project (B507).

语种：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.