A new class of naphthalimide-based antitumor agents that inhibit topoisomerase II and induce lysosomal membrane permeabilization and apoptosis.
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 microM and are more active than amonafide, a naphthalimide 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.
Chen
Zhuo
Z
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Liang
Xin
X
Zhang
Huanying
H
Xie
Hua
H
Liu
Jianwen
J
Xu
Yufang
Y
Zhu
Weiping
W
Wang
Yi
Y
Wang
Xin
X
Tan
Shaoying
S
Kuang
Dong
D
Qian
Xuhong
X
D000225:Adenine; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D015195:Drug Design; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D053644:Naphthalimides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D063065:Organophosphonates; D010539:Permeability / Q000187:drug effects; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D053644:Naphthalimides; D063065:Organophosphonates; D059005:Topoisomerase II Inhibitors; C037020:amonafide; D004247:DNA; D004250:DNA Topoisomerases, Type II; D000225:Adenine