Dinuclear Copper(I) Complexes Containing Cyclodiphosphazane Derivatives and Pyridyl Ligands: Synthesis, Structural Studies, and Antiproliferative Activity toward Human Cervical and Breast Cancer Cells

Abstract

Several mixed-ligand copper(I) complexes of cyclodiphosphazanes, [(t)BuNP(NC(4)H(8)X)](2) (1, X = O; 2, X = NMe), were synthesized by reacting the octanuclear copper(I) complexes [Cu(8)(μ(2)-I)(8){[(t)BuNP(NC(4)H(8)X)](2)}(4)] (3, X = O; 4, X = NMe) with various pyridyl ligands. Interaction of the metallomacrocyclic complex 3 or 4 with pyridine, 2,2'-bipyridine, and 1,10-phenanthroline afforded the neutral dinuclear complexes [(C(5)H(5)N)(4)Cu(2)I(2){[(t)BuNP(NC(4)H(8)X)](2)}] (5, X = O; 6, X = NMe), [(2,2'-bpy)(2)Cu(2)I(2){[(t)BuNP(NC(4)H(8)X)](2)}] (7, X = O; 8, X = NMe), and [(1,10-phen)(2)Cu(2)I(2){[(t)BuNP(NC(4)H(8)X)](2)}] (9, X = O; 10, X = NMe), respectively, in good yield. The new dinuclear complexes 3, 5, and 7-9 were tested for their cytotoxic properties against human cervical cancer (HeLa) cells. The results indicated that all of the copper complexes have in vitro antitumor activity either similar to or better than that of cisplatin, a widely used anticancer drug. Among the compounds tested, complex 9 showed the most potent inhibitory activity in HeLa cells. In addition, complex 9 was found to potently inhibit proliferation of human breast cancer cells (MCF-7), highly metastatic breast cancer cells (MDA-MB 231), and nontransformed Chinese hamster ovary (CHO) cells. Complex 9 inhibited proliferation of these cells in culture more potently than cisplatin; for example, complex 9 was found to inhibit proliferation of HeLa and MCF-7 cells 3 and 5 times more efficiently than cisplatin. Complex 9 treatment damaged the DNA integrity, blocked the cells in the G1 phase of the cell cycle, and induced apoptosis via a p53-dependent pathway. The molecular structures of complexes 9 and 10 were confirmed by single-crystal X-ray diffraction studies.

Biological activity and structure dependent properties of cuprous iodide complexes with phenanthrolines and water soluble tris (aminomethyl) phosphanes

“…First, phosphanes derived from aminoacids [6][7][8][9] or prepared from the highly water-soluble aliphatic secondary amines [10] seem to be most interesting in terms of formation of potential conjugates with a wide range of biomolecules. Second, a number of copper(I) complexes with tertiary phosphanes and diphosphanes showed a promising biological activity [11][12][13][14][15][16][17][18][19][20]. Additionally, it has been proven, that the use of the water soluble phosphanes is reasonable because their hydrophilic and labile complexes with copper(I) are more active against a panel of human tumor cell lines than the complexes with chelating diphosphanes [4,12].…”

Characterization of antiproliferative potential and biological targets of a copper compound containing 4′-phenyl terpyridine

“…Copper is present in all living organisms and is essential for growth and development, oxidative phosphorylation and DNA synthesis [3,4]. Being a vital element, the use of copper as anticancer agent supposedly causes lower toxicity than non-essential metals, such as platinum [4,5]. The properties of copper complexes are determined by the nature of chelates, which could have antiproliferative activity themselves [4,6].…”

“…Copper complexes with pyridyl ligands, like 2,2′-bipyridine and 1,10-phenanthroline, form stable chelates with moderate antiproliferative activity [5]. Other ligands, such as terpyridine, are also able to improve the stability of copper complexes and promote insertion of either planar pyridyl or aromatic ring between base pairs of the DNA, where the copper acts both as an anchor and reactive agent [5,16,17].…”

“…Other ligands, such as terpyridine, are also able to improve the stability of copper complexes and promote insertion of either planar pyridyl or aromatic ring between base pairs of the DNA, where the copper acts both as an anchor and reactive agent [5,16,17]. Considering copper and terpyridine properties, the synthesis and chemical characterization of a copper compound [Cu(H 2 O){OS(CH 3 ) 2 }L](NO 3 ) 2 incorporating the ligand 4′-phenyl-terpyridine (l) (named ZM5 in this work) (Fig.…”

Copper(II) complexes of terpyridine derivatives: A footstep towards development of antiproliferative agent for breast cancer

“…However, the concentration of copper in cancerous tissues such as breast, prostate, lung, and brain, is higher than that of the normal tissues [32][33][34]. Recently it has been reported that pyridyl-type ligand [35] and copper(II) terpyridyl complexes show moderate anticancer activities [36,37]. Complexes of these ligands would be good candidates for examination of their effect on cell proliferation.…”