Design and synthesis of the novel DNA topoisomerase II inhibitors: esterification and amination substituted 4'-demethylepipodophyllotoxin derivates exhibiting anti-tumor activity by activating ATM/ATR signaling pathways.

Abstract

According to the structure-activity relationship, drug combination principle and bioisosterism, a series of the novel esterification and amination 4'-demethylepipodophyllotoxin derivates were rationally designed in order to discover the potential antitumor prodrug. And then these compounds were tested by the drug-topoisomerase II docking models for virtual screening. Thus, twelve target compounds were screened out and synthesized. Most of compounds exhibited promising in vitro anti-tumor activity, particularly 4-N-tris(hydroxymethyl)metylaminomethane-4-deoxy-4'-demethylepipodophyllotoxin (Compound 1). The anti-tumor activity of Compound 1 against the tumor cell lines BGC-823 (i.e., the IC50 value of 5.35 ± 0.77 μM), HeLa (i.e., the IC50 value of 160.48 ± 14.50 μM), and A549 (i.e., the IC50 value of 13.95 ± 5.41 μM) was significantly improved by 706%, 31% and 900% than that of etoposide (i.e., the IC50 values of 43.74 ± 5.13, 209.90 ± 13.42, and 139.54 ± 7.05 μM), respectively. Moreover, the IC50 value of Compound 1 against the normal human cell line HK-2 (i.e., 16.3 ± 3.77 μM) was 78% lower than that of etoposide (i.e., 9.17 ± 1.58 μM). Compound 1 could diminish the relaxation reaction topoisomerase II DNA decatenation at a concentration of 10 μM and induce BGC-823 apoptosis by breaking DNA double-strand and activating ATM/ATR signaling pathways.

• Authors: Li Xiao, Wei Zhao, Hong-Mei Li, Duan-Ji Wan, Dong-Sheng Li, Tao Chen, Ya-Jie Tang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 80 Pg. 267-77 (Jun 10 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 24793877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Topoisomerase II Inhibitors
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• DNA Topoisomerases, Type II
• Podophyllotoxin
• 4'-demethylepipodophyllotoxin

Topics

• Amination
• Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Catalytic Domain
• Cell Line, Tumor
• DNA Topoisomerases, Type II (chemistry, metabolism)
• Drug Design
• Humans
• Molecular Docking Simulation
• Podophyllotoxin (analogs & derivatives, chemical synthesis, chemistry, metabolism, pharmacology)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Topoisomerase II Inhibitors (chemical synthesis, chemistry, metabolism, pharmacology)