A series of alpha-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIalpha catalytic activity

He Huang; Qin Chen; Xin Ku; Linghua Meng; Liping Lin; Xiang Wang; Caihua Zhu; Yi Wang; Zhi Chen; Ming Li; Hualiang Jiang; Kaixian Chen; Jian Ding; Hong Liu

doi:10.1021/jm9014394

A series of alpha-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIalpha catalytic activity

J Med Chem. 2010 Apr 22;53(8):3048-64. doi: 10.1021/jm9014394.

Authors

He Huang¹, Qin Chen, Xin Ku, Linghua Meng, Liping Lin, Xiang Wang, Caihua Zhu, Yi Wang, Zhi Chen, Ming Li, Hualiang Jiang, Kaixian Chen, Jian Ding, Hong Liu

Affiliation

¹ 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.

PMID: 20353152
DOI: 10.1021/jm9014394

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / metabolism
Adenosine Triphosphate / metabolism
Aldehydes / chemical synthesis*
Aldehydes / chemistry
Aldehydes / pharmacology
Animals
Antigens, Neoplasm
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Biocatalysis
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
DNA Topoisomerases, Type II
DNA-Binding Proteins / antagonists & inhibitors*
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Humans
Hydrolysis
Iron Chelating Agents / chemical synthesis*
Iron Chelating Agents / chemistry
Iron Chelating Agents / pharmacology
Mice
Models, Molecular
Neoplasm Transplantation
Protein Binding
Protein Structure, Tertiary
Structure-Activity Relationship
Thiosemicarbazones / chemical synthesis*
Thiosemicarbazones / chemistry
Thiosemicarbazones / pharmacology
Topoisomerase II Inhibitors*

Substances

2-(quinolin-2-ylmethylene)hydrazinecarbothioamide
Aldehydes
Antigens, Neoplasm
Antineoplastic Agents
DNA-Binding Proteins
Iron Chelating Agents
Thiosemicarbazones
Topoisomerase II Inhibitors
Adenosine Triphosphate
Adenosine Triphosphatases
DNA Topoisomerases, Type II