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Eur J Med Chem. 2018 Aug 5;156:368-380. doi: 10.1016/j.ejmech.2018.07.022. Epub 2018 Jul 10.

Mixed-ligand Cu(II) hydrazone complexes designed to enhance anticancer activity.

Author information

1
Affiliated Hospital, Guilin Medical University, Guilin, Guangxin, China; School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
2
Affiliated Hospital, Guilin Medical University, Guilin, Guangxin, China.
3
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
4
School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
5
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China.
6
School of Pharmacy, Nantong University, Nantong, Jiangsu, China. Electronic address: sanchuanok@126.com.
7
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China. Electronic address: fyang@mailbox.gxnu.edu.cn.

Abstract

The ligand quantity, ligand type, and coordination geometry have important influences on the anticancer activity of metal-based complexes. On the basis of the structures of previously reported 1:1 Cu(II)/ligand complexes ([Cu(L1)Cl]·2H2O 1a, [Cu(L2)Cl]·H2O 2a, and [Cu(L2)NO3]·H2O 3a), we subsequently designed, developed, and characterized a series of corresponding 1:1:1 Cu(II)/ligand/co-ligand complexes ([Cu(L1)(Py)Cl]·H2O 1b, [Cu(L2)(Py)Cl] 2b, and [Cu(L2)(Py)NO3] 3b), where L1 = (E)-N'-(2-hydroxybenzylidene)acetohydrazide, L2 = (E)-N'-(2- hydroxybenzylidene)benzohydrazide, and Py = pyridine. All six Cu(II) complexes were assessed for their in vitro anticancer properties against a panel of human cancer cells, including cisplatin-resistant A549cisR cell lines. Interestingly, we observed that the 1:1:1 Cu/ligand/co-ligand mixed-ligand Cu(II) complexes exhibited higher anticancer activity than the corresponding 1:1 Cu(II)/ligand complexes. In particular, the 1:1:1 Cu(II)/ligand/co-ligand complex 3b displayed the greatest toxicity toward several cancer cells with better IC50 (1.12-3.77 μM) than cisplatin. Further mechanistic explorations showed that the 3b complex induced DNA damage, thus resulting in mitochondria-mediated apoptotic cell death. Furthermore, the 3b complex displayed pronounced cytostatic effects in the MCF-7 3D spheroid model.

KEYWORDS:

Anticancer activity; Anticancer mechanism; Mixed-ligand copper(II) complexes; Spheroid assay

PMID:
30015073
DOI:
10.1016/j.ejmech.2018.07.022
[Indexed for MEDLINE]

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