Oxidative DNA Cleavage, Formation of μ-1,1-Hydroperoxo Species, and Cytotoxicity of Dicopper(II) Complex Supported by a p-Cresol-Derived Amide-Tether Ligand
Abstract:Metal complexes to promote oxidative DNA cleavage by H 2 O 2 are desirable as anticancer drugs. A dicopper(II) complex of known p-cresol-derived methylene-tether ligand Hbcc [Cu 2 (bcc)] 3+ did not promote DNA cleavage by H 2 O 2 . Here, we synthesized a new p-cresol-derived amide-tether one, 2,6-bis(1,4,7,10tetrazacyclododecyl-1-carboxyamide)-p-cresol (Hbcamide). A dicopper(II) complex of the new ligand [Cu 2 (μ-OH)(bcamide)] 2+ was structurally characterized. This complex promoted the oxidative cleavage of s… Show more
“…The mechanism for double-strand cleavage by a single BLM molecule would then involve the Fe IV intermediate generated by the first reaction as the active species for the initial second H-atom abstraction reaction damaging the second DNA strand. A hydroperoxo species of the dicopper(II) was also identified as the active species and spectroscopically identified in the reaction of the complex with plasmids (Kadoya et al, 2019). Analogical investigations for the dirhenium(III) complexes are absent, but acceleration of the nuclease reaction by hydrogen peroxide shown by us makes possible to think that the same hydroperoxo species may play definite role in the investigating processes with rhenium substances.…”
Section: Resultsmentioning
confidence: 70%
“…To study cleavage ability of metal-containing substances and their cleavage pathway, an assay is widely used, which employs a special type of DNA, a plasmid DNA (Wang et al, 2015;Kettenman et al, 2018;Kadoya et al, 2019). Single strand DNA cleavage (SSC) is the process, in which one scission is introduced in one of the two DNA strands in one cleavage event.…”
Section: Resultsmentioning
confidence: 99%
“…Supercoiled DNA is often referred to as form I, nicked DNA as form II and linear DNA as form III. These forms are good resolved by electrophoresis (Sears et al, 2013;Kadoya et al, 2019). We used these good described phenomena to investigate cleaving activity of the investigated substances II and III ( Fig.…”
The DNA-interactions in vitro are still necessary investigations for determination of the possible anticancer properties of the compounds, candidates for application in cancer therapy. The aim of the present work was to realize if the interaction of cis-dicarboxylates of dirhenium(III), with pivalato- (I), isobutirato- (II) and adamanthyl- (III) ligands cleaves the plasmid in the same manner and what is the influence of the ligands on this process. For experiments we used the prokaryotic plasmid which is good model to analyze DNA-cleaving ability of different substances that exists in supercoiled conformation and turns to nicked and linear forms. It was shown that gradual conversion of the supercoiled Form I to a mixture of supercoiled (Form I) and nicked (Form II) DNA takes place and increasing amounts of Form II are produced with higher concentrations of I–III under increasing of concentration that showed the DNA-cleaving abilities of all investigated dirhenium complexes. This process was taking place with different intensity in the range I ˃ II ˃ III, that demonstrates the influence of the organic radical on the cleaving activity of the dirhenium(III) complexes. Under hydrogen peroxide conditions, I and II showed close results, demonstrating more intensive process of cleaving, including formation of the linear plasmid (Form III) under higher concentration, witnessing about redox-activation of the DNA-cleaving reaction. Cleaving activity of III was approximately the same in all experiments, that was demonstrated only by decreasing of the supercoiled form I and increasing of the nicked form II of the plasmid and by absolutely absence of the linear form III of the plasmid. The electrophoresis mobility shift assays showed that rhenium cluster compounds have nuclease activity and confirmed that natural DNA may be their target in the living cells. The conclusion was made that the mechanism of DNA-cleavage reaction of the dirhenium(III) complexes is multiple in which the electron donating (withdrawing) effects of the ligands and catalytic activity of the metal core should be taken in consideration.
“…The mechanism for double-strand cleavage by a single BLM molecule would then involve the Fe IV intermediate generated by the first reaction as the active species for the initial second H-atom abstraction reaction damaging the second DNA strand. A hydroperoxo species of the dicopper(II) was also identified as the active species and spectroscopically identified in the reaction of the complex with plasmids (Kadoya et al, 2019). Analogical investigations for the dirhenium(III) complexes are absent, but acceleration of the nuclease reaction by hydrogen peroxide shown by us makes possible to think that the same hydroperoxo species may play definite role in the investigating processes with rhenium substances.…”
Section: Resultsmentioning
confidence: 70%
“…To study cleavage ability of metal-containing substances and their cleavage pathway, an assay is widely used, which employs a special type of DNA, a plasmid DNA (Wang et al, 2015;Kettenman et al, 2018;Kadoya et al, 2019). Single strand DNA cleavage (SSC) is the process, in which one scission is introduced in one of the two DNA strands in one cleavage event.…”
Section: Resultsmentioning
confidence: 99%
“…Supercoiled DNA is often referred to as form I, nicked DNA as form II and linear DNA as form III. These forms are good resolved by electrophoresis (Sears et al, 2013;Kadoya et al, 2019). We used these good described phenomena to investigate cleaving activity of the investigated substances II and III ( Fig.…”
The DNA-interactions in vitro are still necessary investigations for determination of the possible anticancer properties of the compounds, candidates for application in cancer therapy. The aim of the present work was to realize if the interaction of cis-dicarboxylates of dirhenium(III), with pivalato- (I), isobutirato- (II) and adamanthyl- (III) ligands cleaves the plasmid in the same manner and what is the influence of the ligands on this process. For experiments we used the prokaryotic plasmid which is good model to analyze DNA-cleaving ability of different substances that exists in supercoiled conformation and turns to nicked and linear forms. It was shown that gradual conversion of the supercoiled Form I to a mixture of supercoiled (Form I) and nicked (Form II) DNA takes place and increasing amounts of Form II are produced with higher concentrations of I–III under increasing of concentration that showed the DNA-cleaving abilities of all investigated dirhenium complexes. This process was taking place with different intensity in the range I ˃ II ˃ III, that demonstrates the influence of the organic radical on the cleaving activity of the dirhenium(III) complexes. Under hydrogen peroxide conditions, I and II showed close results, demonstrating more intensive process of cleaving, including formation of the linear plasmid (Form III) under higher concentration, witnessing about redox-activation of the DNA-cleaving reaction. Cleaving activity of III was approximately the same in all experiments, that was demonstrated only by decreasing of the supercoiled form I and increasing of the nicked form II of the plasmid and by absolutely absence of the linear form III of the plasmid. The electrophoresis mobility shift assays showed that rhenium cluster compounds have nuclease activity and confirmed that natural DNA may be their target in the living cells. The conclusion was made that the mechanism of DNA-cleavage reaction of the dirhenium(III) complexes is multiple in which the electron donating (withdrawing) effects of the ligands and catalytic activity of the metal core should be taken in consideration.
“…Thus, the cleavage activity of artificial nucleases is their practical ability to convert the SC form into OC and/or L forms [23] , [127] . In order to gain further insight and identify possible ROS into the cleavage mechanism, reactions performed with ROS-specific scavengers/quenchers for example potassium iodide (KI) as a H 2 O 2 scavenger, DMSO and EtOH as hydroxyl radical scavengers, sodium azide (NaN 3 ) as a singlet oxygen quencher, superoxide dismutase (SOD) as the superoxide anion radical scavenger, and pyruvate as a hydrogen peroxide scavenger [27] , [28] , [29] , [30] , [31] . Fig.…”
Section: Models Substrates and Instrumentations Employedmentioning
confidence: 99%
“…Nevertheless, therapeutic potentials of AMSs have not received a substantially deep attention, we therefore try here to highlight the recent progress conducted on the metal complexes employed in mimetic cleavage studies of nucleic acids and shed a light on their potential therapeutic applications. Metal complexes possess rich structural and electronic properties as well as redox-active centers which enable them to cleave nucleic acids through hydrolysis [27] , [28] and/or by generating reactive oxygen species (ROS) (oxidative cleavage and photocleavage) [29] , [30] , [31] , [32] , [33] . A rich library of DNA/RNA–cleaving metal complexes have been prepared and submitted to pharma studies as novel therapeutic candidates for the treatment of diseases such as cancer [13] , [14] , [34] , [35] , [36] , [37] , [38] , [39] , bacterial [13] , [14] , [39] , [40] , [41] , [42] , [43] , [44] , [45] and viral infections [13] , [14] , [46] , [47] , [48] , [49] , and gene therapy [50] , [51] .…”
Despite the extensive and rapid discovery of modern drugs for treatment of cancer, microbial infections, and viral illnesses; these diseases are still among major global health concerns. To take inspiration from natural nucleases and also the therapeutic potential of metallopeptide antibiotics such as the bleomycin family, artificial metallonucleases with the ability of promoting DNA/RNA cleavage and eventually affecting cellular biological processes can be introduced as a new class of therapeutic candidates. Metal complexes can be considered as one of the main categories of artificial metalloscissors, which can prompt nucleic acid strand scission. Accordingly, biologists, inorganic chemists, and medicinal inorganic chemists worldwide have been designing, synthesizing and evaluating the biological properties of metal complexes as artificial metalloscissors. In this review, we try to highlight the recent studies conducted on the nuclease-like metalloscissors and their potential therapeutic applications. Under the light of the concurrent Covid-19 pandemic, the human need for new therapeutics was highlighted much more than ever before. The nuclease-like metalloscissors with the potential of RNA cleavage of invading viral pathogens hence deserve prime attention.
Bis(macrocyclic) complexes are investigated as artificial analogues of natural dinuclear metalloenzymes. Two ligands containing two cyclam rings connected through a cresol or 4‑nitrophenol spacer were synthesized and their complexing properties were investigated. CuII complexes were prepared and their properties were studied by a combination of spectral, diffraction and electrochemical methods. The phenolate group is not or only weakly coordinated to the central CuII ion and the two macrocycles behave mostly as two independent complexing units. All the determined solid‐state structures showed cyclam adopting trans‐III geometry, however, solution study indicated the presence of more isomers in the solution whose abundance changes with pH. Electrochemical reduction of the complexes is irreversible and results in the reductive decomplexation to amalgamated Cu metal. The amalgamated metal is re‐oxidized to CuII during the anodic scan of CV and the metal ion is re‐coordinated. The ligand containing the nitro group shows an irreversible four‐electron reduction of the nitro group. The ligands and the complexes undergo also a slow degradation when incubated in the aqueous solutions for a prolonged time. The degradation relies on the “retro‐Mannich” cleavage of the methylene bridge connecting the cyclam ring with the phenol moiety.
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