Dicopper(II) Complexes of p-Cresol-2,6-Bis(dpa) Amide-Tether Ligands: Large Enhancement of Oxidative DNA Cleavage, Cytotoxicity, and Mechanistic Insight by Intracellular Visualization

Abstract

Dicopper complexes of a new p-cresol-2,6-bis(dpa) amide-tether ligand (HL1), [Cu 2 (μ-OH 2 )(μ-1,3-OAc)(L1)](ClO 4 ) 2 (1) and [Cu 2 (μ-1,1-OAc)(μ-1,3-OAc)(L1)]X (X = ClO 4 (2a), OAc (2b)) were synthesized and structurally characterized. 2b rapidly cleaves supercoiled plasmid DNA by activating H 2 O 2 at neutral pH to a linear DNA and shows remarkable cytotoxicity in comparison with related complexes. As 2b is more cytotoxic than HL1, the dicopper core is kept in the cell. A boron dipyrromethene (Bodipy)-modified complex of the p-cresol-2,6-bis(dpa) amide-tether ligand having a Bodipy pendant (HL2), [Cu 2 (μ-OAc) 2 (L2)](OAc) (3), was synthesized to visualize intracellular behavior, suggesting that 2b attacks the nucleolus and mitochondria. A comet assay clearly shows that 2b does not cleave nuclear DNA. The apoptotic cell death is evidenced from flow cytometry.

Enhancement of cancer-cell-selective cytotoxicity by a dicopper complex with a phenanthrene amide-tether ligand conjugate via mitochondrial apoptosis

“…In terms of cancercell selectivity, 1 is seven times more selective than a dicopper complex with a p-cresol-amide-tether-dpa ligand. 14 These results indicate that cancer-cell-selectivity depends on the ligand and coordination structure of the dicopper core, and that the toxicity of 1 is enhanced by the DNA-targeting phenanthrene unit independently.…”

“…N,N′,N″-4,7,10-Tris(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecane (5), 4-(N-(8-azido-3,6-dioxaoctyl)carbamoyl)-2-hydroxyisophthalic acid (9), and complex 2 were prepared according to the literature. 13,14,[23][24][25]…”

“…A dicopper complex of this ligand largely improved DNA cleavage activity and cytotoxicity, but the cancer-cellselectivity was insufficient. 14 In this study, to enhance the DNA-cleavage activity and toxicity by mimicking the role of a DNA-binding site of bleomycin, [15][16][17] we synthesized a novel phenanthrene amide-tether ligand HL1 where a phenanthrene unit is attached to HL2 by an ethylene glycol spacer (Scheme 1). HL1 forms dicopper complex [Cu 2 (μ-OH)(L1)](ClO 4 ) 2 (1).…”

Terpyridine copper(ii) complexes as potential anticancer agents by inhibiting cell proliferation, blocking the cell cycle and inducing apoptosis in BEL-7402 cells

“…All these results showed that complexes 1-4 could induce apoptosis in the Bel-7402 cells. 49 Fig. 3 Effects of the cell cycle treated with complex 1.…”

Nuclease-like metalloscissors: Biomimetic candidates for cancer and bacterial and viral infections therapy

“…Of course, the ultimate goal of this diversity lies in the enhancement of the AMSs’ biological activity. Accordingly, these actively ongoing techniques are categorized as follow: i) Preparation of multinuclear complexes wherein the metal cores cooperate to provides an efficient active binding site for biomolecules [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] . ii) Variation of the first coordination sphere towards synthesis of homoleptic and hetroleptic complexes [66] , [67] , [68] , [69] , [70] , [71] .…”