Copper (II) complexes possessing alkyl-substituted polypyridyl ligands: Structural characterization and in vitro antitumor activity

• Published in: Journal of inorganic biochemistry Vol. 166; pp. 12 - 25
• Main Authors: Angel, Noah R., Khatib, Raneen M., Jenkins, Julia, Smith, Michelle, Rubalcava, Justin M., Le, Brian Khoa, Lussier, Daniel, Chen, Zhuo (Georgia), Tham, Fook S., Wilson, Emma H., Eichler, Jack F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2017
• Subjects: A549 Cells; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bipyrydine; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Copper - pharmacology; Copper(II); Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Phenanthroline; Polypyridyl; Pyridines - chemistry; Pyridines - pharmacology; Synthesis; Polypyridyl; Synthesis; Phenanthroline; Anticancer; Bipyrydine; Copper(II)
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.09.012

In an effort to find alternatives to the antitumor drug cisplatin, a series of copper (II) complexes possessing alkyl-substituted polypyridyl ligands have been synthesized. Eight new complexes are reported herein: μ-dichloro-bis{2,9-di-sec-butyl-1,10-phenanthrolinechlorocopper(II)} {[(di-sec-butylphen)ClCu(μ-Cl)2CuCl(di-sec-butylphen)]}(1), 2-sec-butyl-1,10-phenanthrolinedichlorocopper(II) {[mono-sec-butylphen) CuCl2} (2), 2,9-di-n-butyl-1,10-phenanthrolinedichlorocopper(II) {[di-n-butylphen) CuCl2}(3), 2-n-butyl-1,10-phenanthrolinedichlorocopper(II) {[mono-n-butylphen) CuCl2} (4), 2,9-di-methyl-1,10-phenanthrolineaquadichlorocopper(II) {[di-methylphen) Cu(H2O)Cl2}(5), μ-dichloro-bis{6-sec-butyl-2,2′-bipyridinedichlorocopper(II)} {(mono-sec-butylbipy) ClCu(μ-Cl)2CuCl(mono-sec-butylbipy)} (6), 6,6′-di-methyl-2,2′-bipyridinedichlorocopper(II) {6,6′-di-methylbipy) CuCl2} (7), and 4,4′-dimethyl-2,2′-bipyridinedichlorocopper(II) {4,4′-di-methylbipy) CuCl2} (8). These complexes have been characterized via elemental analysis, UV–vis spectroscopy, and mass spectrometry. Single crystal X-ray diffraction experiments revealed the complexes synthesized with the di-sec-butylphen ligand (1) and mono-sec-butylbipy ligand (6) crystallized as dimers in which two copper(II) centers are bridged by two chloride ligands. Conversely, complexes 2, 7, and 8 were isolated as monomeric species possessing distorted tetrahedral geometries, and the [(di-methylphen)Cu(H2O)Cl2] (5) complex was isolated as a distorted square pyramidal monomer possessing a coordinating aqua ligand. Compounds 1–8 were evaluated for their in vitro antitumor efficacy. Compounds 1, 5, and 7 in particular were found to exhibit remarkable activity against human derived lung cancer cells, yet this class of copper(II) compounds had minimal cytotoxic effect on non-cancerous cells. In vitro control experiments indicate the activity of the copper(II) complexes most likely does not arise from the formation of CuCl2 and free polypyridyl ligand, and preliminary solution state studies suggest these compounds are generally stable in biological buffer. The results presented herein suggest further development of this class of copper-based drugs as potential anti-cancer therapies should be pursued. Treatment of lung cancer cell line A549 with of alkyl-substituted polypyridyl copper(II) complexes shows promising antiproliferative activity as well as a high degree of selectivity for cancerous cells over benign somatic cells. [Display omitted] •Eight new copper(II) coordination complexes synthesized and characterized•Copper(II) complexes possess alky-substituted 1,10-phenanthroline and 2,2′-bipyridine ligands.•Five copper(II) complexes characterized by single crystal X-ray diffraction•Three distorted tetrahedral, one distorted square pyramidal, and one dimeric complex described•Copper(II) complexes exhibit general in-vitro antitumor activity against lung tumor cells.