Copper-Activated DNA Photocleavage by a Pyridine-Linked Bis-Acridine Intercalator

Abstract

We report the synthesis of new photonuclease 4 consisting of two acridine rings joined by a pyridine-based copper binding linker. We have shown that photocleavage of plasmid DNA is markedly enhanced when this ligand is irradiated in the presence of copper(II) (419 nm, 22 degrees C, pH 7.0). Viscometric data indicate that 4 binds to DNA by monofunctional intercalation, and equilibrium dialysis provides an estimated binding constant of 1.13 x 105 M-1 for its association with calf thymus DNA. In competition dialysis experiments, 4 exhibits preferential binding to GC-rich DNA sequences. When Cu(II) is added at a ligand to metal ratio of 1:1, electrospray ionization mass spectrometry demonstrates that compound 4 undergoes complex formation, while thermal melting studies show a 10 degrees C increase in the Tm of calf thymus DNA. Groove binding and intercalation are suggested by viscometric data. Finally, colorimetric and scavenger experiments indicate that the generation of Cu(I), H2O2, and superoxide contributes to the production of DNA frank strand breaks by the Cu(II) complex of 4. Whereas the strand breaks are distributed in a relatively uniform fashion over the four DNA bases, subsequent piperidine treatment of the photolysis reactions shows that alkaline labile lesions occur predominantly at guanine.

DNA Cleavage by Structurally Characterized Dinuclear Copper(II) Complexes Based on Triazine

“…The significant increase in the DNA cleavage activity by 2 in the presence of H 2 O 2 and the inhibition of activity in the presence of DMSO and KI suggest that this reaction is preferentially proceeding by a hydroxy radical mechanism with · OH and hydrogen peroxide species. The oxidative reaction pathway observed here has been suggested previously in the vast majority of DNA cleavage activity by copper complexes [14,15,48,[51][52][53][54][55][56] and in the DNA photocleavage activity by some cobalt(III) complexes. [57] The rate enhancement for DNA cleavage by 2 or its hydrolytic active species [Cu 2 (μ-bdpaT Cl )(H 2 O) 3 Cl] 3+ corresponding to a 2.5 ϫ 10 6 fold increase over the noncatalyzed DNA (k = 1.0 ϫ 10 -11 s -1 at 37°C) [58] reveals the efficiency of this complex to cleave DNA.…”

“…Comparable and even higher enhancements by copper(II) complexes have been reported for DNA cleavage when rates were compared at the saturation levels under pseudo-Michaelis-Menten kinetics. [46,47,51,55] Under similar physiological conditions, the trinuclear copper(II) complex [Cu 3 (TDAT) 2 Cl 3 ]Cl 3 ·2H 2 O derived from 2,4,6-tris(di-2-pyridylamine)-1,3,5-triazine (TDAT) also exhibited efficient oxidative DNA cleavage. [56] The lack of DNA cleavage activity by the bridged dihydroxido complex 1 does not seem to be unusual in light of the short Cu···Cu distance of 2.9808(9) Å in the bridging moiety of the Cu(μ-OH) 2 Cu unit.…”

Synthesis, structure, DNA binding and DNA cleavage activity of oxovanadium(IV) N-salicylidene-S-methyldithiocarbazate complexes of phenanthroline bases

“…Bleomycin is an anticancer drug that works as a chemical nuclease showing oxidative cleavage of DNA [21,22]. There are recent reports of transition metal complexes cleaving DNA on photo-irradiation in visible light [23][24][25][26][27][28][29][30]. The complexes showing facile visible light-induced cleavage of DNA are of interest in the chemistry of photodynamic therapy (PDT) of cancer [7,8].…”

Synthesis and copper-mediated nuclease activity of a tetracationic tris(2,2′-bipyridine) ligand

“…A synergistic effect was observed only for one of these compounds, while the others did not present synergism [20,21]. Moreover, we have also described the nuclease activity of copper complex-intercalator conjugates [22][23][24]. Heterocyclic compounds such as 1,10-phenantroline and 2,2 0 -bipyridine can form different metal complexes and have been extensively studied for their nuclease-like activity.…”