title: 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.affiliation: Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Li
authors.affiliation: Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China.
authors.forename: Duan-Ji
authors.initials: DJ
authors.lastname: Wan
authors.affiliation: Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Li
authors.affiliation: Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, China; Stake Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: yajietang@hotmail.com.
authors.forename: Ya-Jie
authors.initials: YJ
authors.lastname: Tang
mesh_terms: D000586:Amination; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin; C072088:4'-demethylepipodophyllotoxin
keywords: 4′-Demethylepipodophyllotoxin derivates; ATM/ATR signaling pathway; Anti-tumor activity; Apoptosis; Structure–activity relationships; Topoisomerase II