A new class of naphthalimide-based antitumor agents that inhibit topoisomerase II and induce lysosomal membrane permeabilization and apoptosis.

Abstract

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.

• Authors: Zhuo Chen, Xin Liang, Huanying Zhang, Hua Xie, Jianwen Liu, Yufang Xu, Weiping Zhu, Yi Wang, Xin Wang, Shaoying Tan, Dong Kuang, Xuhong Qian
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 6 Pg. 2589-600 (Mar 25 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20170164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Naphthalimides
• Organophosphonates
• Topoisomerase II Inhibitors
• amonafide
• DNA
• DNA Topoisomerases, Type II
• Adenine

Topics

• Adenine
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Binding, Competitive
• Cell Line, Tumor
• Cell Survival (drug effects)
• Circular Dichroism
• DNA (genetics, metabolism)
• DNA Topoisomerases, Type II (metabolism)
• Drug Design
• HL-60 Cells
• HeLa Cells
• Humans
• Inhibitory Concentration 50
• Intracellular Membranes (drug effects, metabolism)
• Lysosomes (metabolism)
• Models, Chemical
• Molecular Structure
• Naphthalimides (chemistry, metabolism, pharmacology)
• Organophosphonates
• Permeability (drug effects)
• Plasmids (genetics, metabolism)
• Spectrometry, Fluorescence
• Structure-Activity Relationship
• Topoisomerase II Inhibitors