In vitro and in vivo antitumor activities of Ru and Cu complexes with terpyridine derivatives as ligands

Yang Yang; Cai-Feng Chen; Fei-Fei Guo; Yun-Qiong Gu; Hong Liang; Zhen-Feng Chen

doi:10.1016/j.jinorgbio.2023.112284

In vitro and in vivo antitumor activities of Ru and Cu complexes with terpyridine derivatives as ligands

J Inorg Biochem. 2023 Sep:246:112284. doi: 10.1016/j.jinorgbio.2023.112284. Epub 2023 Jun 5.

Authors

Yang Yang¹, Cai-Feng Chen², Fei-Fei Guo², Yun-Qiong Gu³, Hong Liang⁴, Zhen-Feng Chen⁵

Affiliations

¹ State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China; Department of Chemistry and Pharmacy, Guilin Normal College, Guilin 541004, China.
² State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
³ State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China; School of Environment and Life Science, Nanning Normal University, Nanning 530001, China.
⁴ State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: hliang@gxnu.edu.cn.
⁵ State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China. Electronic address: chenzf@gxnu.edu.cn.

PMID: 37327592
DOI: 10.1016/j.jinorgbio.2023.112284

Abstract

Six terpyridine ligands(L¹-L⁶) with chlorophenol or bromophenol moiety were obtained to prepare metal terpyridine derivatives complexes: [Ru(L¹)(DMSO)Cl₂] (1), [Ru(L²)(DMSO)Cl₂] (2), [Ru(L³)(DMSO)Cl₂] (3), [Cu(L⁴)Br₂]·DMSO (4), Cu(L⁵)Br₂ (5), and [Cu(L⁶)Br₂]⋅CH₃OH (6). The complexes were fully characterized. Ru complexes 1-3 showed low cytotoxicity against the tested cell lines. Cu complexes 4-6 exhibited higher cytotoxicity against several tested cancer cell lines compared to their ligands and cisplatin, and lower toxicity towards normal human cells. Copper(II) complexes 4-6 arrested T-24 cell cycle in G1 phase. The mechanism studies indicated that complexes 4-6 accumulated in mitochondria of T-24 cells and caused significant reduction of the mitochondrial membrane potential, increase of the intracellular ROS levels and the release of Ca²⁺, and the activation of the Caspase cascade, finally inducing apoptosis. Animal studies showed that complex 6 obviously inhibited the tumor growth in a mouse xenograft model bearing T-24 tumor cells without significant toxicity.

Keywords: Antitumor activity; Crystal structure; Cu complex; Ru complex; Terpyridine derivatives.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Coordination Complexes* / pharmacology
Copper / pharmacology
Dimethyl Sulfoxide / pharmacology
Drug Screening Assays, Antitumor
Humans
Ligands
Mice
Neoplasms*

Substances

Antineoplastic Agents
Copper
Dimethyl Sulfoxide
Ligands
Coordination Complexes