Synthesis, anticancer activity and mechanism of iron chelator derived from 2,6-diacetylpyridine bis(acylhydrazones)

Qian Yao; Jinxu Qi; Yunyun Zheng; Kun Qian; Lai Wei; Mukedasi Maimaitiyiming; Zhen Cheng; Yihong Wang

doi:10.1016/j.jinorgbio.2019.01.003

Synthesis, anticancer activity and mechanism of iron chelator derived from 2,6-diacetylpyridine bis(acylhydrazones)

J Inorg Biochem. 2019 Apr:193:1-8. doi: 10.1016/j.jinorgbio.2019.01.003. Epub 2019 Jan 10.

Authors

Qian Yao¹, Jinxu Qi², Yunyun Zheng³, Kun Qian¹, Lai Wei¹, Mukedasi Maimaitiyiming¹, Zhen Cheng⁴, Yihong Wang⁵

Affiliations

¹ School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
² School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Medical School of Pingdingshan University, Pingdingshan 467000, China.
³ Medical School of Pingdingshan University, Pingdingshan 467000, China.
⁴ Stanford Cancer Institute, Member of Academic Council, Stanford University, USA.
⁵ School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: yihongwang@seu.edu.cn.

PMID: 30654208
DOI: 10.1016/j.jinorgbio.2019.01.003

Abstract

We synthesized five iron chelator derived from 2,6-diacetylpyridine bis(acylhydrazones) and proved their iron complexes structure by X-ray single crystal diffraction. These ligands have a significant anticancer proliferative activity and low cytotoxicity against normal cells. The Fe(III) complexes show reduced cytotoxic activity compared to the metal-free ligands. Anticancer mechanism studies indicate that ligands with a potential anticancer proliferation activity by inhibiting the activity of ribonucleotide reductase. Ligand rather than iron complexes regulate the expression of cell cycle associated proteins and inhibit cell cycle arrest in S phase. Apoptosis mechanism results showed that both ligand and iron complexes did not significantly promote apoptosis.

Keywords: Anticancer activity; Apoptosis; Cell cycle; Chelator; Reactive oxygen species.

Publication types

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

MeSH terms

Antigens, CD / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / toxicity
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Coordination Complexes / chemical synthesis
Coordination Complexes / pharmacology*
Coordination Complexes / toxicity
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / toxicity
Ferritins / metabolism
Humans
Hydrazones / chemical synthesis
Hydrazones / pharmacology*
Hydrazones / toxicity
Iron / chemistry
Iron Chelating Agents / chemical synthesis
Iron Chelating Agents / pharmacology*
Iron Chelating Agents / toxicity
Ligands
Pyridines / chemical synthesis
Pyridines / pharmacology*
Pyridines / toxicity
Receptors, Transferrin / metabolism
Ribonucleotide Reductases / antagonists & inhibitors
S Phase Cell Cycle Checkpoints / drug effects

Substances

Antigens, CD
Antineoplastic Agents
CD71 antigen
Cell Cycle Proteins
Coordination Complexes
Enzyme Inhibitors
Hydrazones
Iron Chelating Agents
Ligands
Pyridines
Receptors, Transferrin
Ferritins
Iron
Ribonucleotide Reductases