title: A series of alpha-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIalpha catalytic activity.
abstract: A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Ku
authors.forename: Linghua
authors.initials: L
authors.lastname: Meng
authors.forename: Liping
authors.initials: L
authors.lastname: Lin
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Caihua
authors.initials: C
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055162:Biocatalysis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006868:Hydrolysis; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: C549333:2-(quinolin-2-ylmethylene)hydrazinecarbothioamide; D000447:Aldehydes; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007502:Iron Chelating Agents; D013882:Thiosemicarbazones; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D004250:DNA Topoisomerases, Type II