title: Synthesis, biological evaluation, and molecular docking study of 3-(3'-heteroatom substituted-2'-hydroxy-1'-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor.
abstract: Epoxide ring-opened xanthone derivatives were synthesized and tested for their topoisomerase inhibitory activity and cytotoxicity. Most of the compounds showed topo IIα specific inhibitory activity. To clarify the mechanism of action of these compounds, the most potent compound (compound 14) of the synthesized analogues was further studied by testing its ATPase inhibitory activity and through molecular docking experiments. The results showed that the topo IIα inhibitory activity of compound 14 was inversely proportional to ATP concentration. In the ATPase inhibitory test, ATP hydrolysis was reduced less efficiently by compound 14 (28.5±4.6%) than novobiocin (60.4±8.1%). Molecular docking study revealed compound 14 to have a stable binding pattern to the ATP-binding domain of human topo II.
authors.affiliation: College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans University, and Severance Hospital Integrative Research Institute for Cerebral & Cardiovascular Disease, Seoul 120-750, Republic of Korea.
authors.forename: Kyu-Yeon
authors.initials: KY
authors.lastname: Jun
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Lee
authors.forename: Mi-Ja
authors.initials: MJ
authors.lastname: Jung
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Lee
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.forename: Hea-Young
authors.initials: HY
authors.lastname: Park Choo
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044004:Xanthones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; D044004:Xanthones; D004250:DNA Topoisomerases, Type II