Synthesis, crystal structure and antiproliferative mechanisms of 2-acetylpyridine-thiosemicarbazones Ga(III) with a greater selectivity against tumor cells

Jinxu Qi; Yunyun Zheng; Kun Qian; Liang Tian; Guo-Xin Zhang; Zhen Cheng; Yihong Wang

doi:10.1016/j.jinorgbio.2017.09.012

Synthesis, crystal structure and antiproliferative mechanisms of 2-acetylpyridine-thiosemicarbazones Ga(III) with a greater selectivity against tumor cells

J Inorg Biochem. 2017 Dec:177:110-117. doi: 10.1016/j.jinorgbio.2017.09.012. Epub 2017 Sep 19.

Authors

Jinxu Qi¹, Yunyun Zheng², Kun Qian³, Liang Tian¹, Guo-Xin Zhang⁴, Zhen Cheng⁵, Yihong Wang⁶

Affiliations

¹ School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
² College of Petroleum and Chemical Engineering, Qinzhou University, Qinzhou, Guangxi, China.
³ School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.; Stanford Cancer Institute, Stanford University, USA.
⁴ Department of Gastroenterology, First Clinical Medical College of Nanjing Medical University, China.
⁵ Stanford Cancer Institute, Stanford University, USA.
⁶ School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.. Electronic address: yihongwang@seu.edu.cn.

PMID: 28946027
DOI: 10.1016/j.jinorgbio.2017.09.012

Abstract

Thiosemicarbazone Ga(III) complexes (C3-C5) were synthesized and characterized by X-ray single crystal diffraction, and they were all 1:1 ligand/Ga(III) complexes. The antiproliferative activity of these Ga(III) complexes was tested against three cancer cell lines, demonstrating that Ga(III) complexes showed about 3-10 folds more anticancer activity than their ligands alone. Importantly, thiosemicarbazones and Ga(III) complexes have a low toxicity to human fetal lung fibroblast cells (MRC-5) and exhibit a high therapeutic index for tumor cells. The results of UV-visible spectroscopy showed that the binding constant of C4 with Topo-I-DNA was significantly higher than that of L4. The Ga(III) complex (C4) caused Topo-I inhibition and distinct DNA cleavage. Moreover, Ga(III) complex and thiosemicarbazone ligand prolonged the G1 phase in NCI-H460 cell cycle, which might be depended on the ability of these compounds to affect the expression of cell cycle related proteins.

Keywords: Antiproliferative; Cell cycle; Gallium (III) complexes; Thiosemicarbazone.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Coordination Complexes / chemical synthesis
Coordination Complexes / chemistry
Coordination Complexes / pharmacology*
Crystallography, X-Ray
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
G1 Phase Cell Cycle Checkpoints / drug effects
Gallium / chemistry*
Humans
Ligands
Molecular Docking Simulation
Molecular Structure
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Thiosemicarbazones / chemical synthesis
Thiosemicarbazones / chemistry
Thiosemicarbazones / pharmacology*
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / pharmacology

Substances

Antineoplastic Agents
Coordination Complexes
Cyclin-Dependent Kinase Inhibitor p21
Ligands
Pyridines
Thiosemicarbazones
Topoisomerase I Inhibitors
Cyclin-Dependent Kinase Inhibitor p27
Gallium