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1.
Dalton Trans ; 52(10): 3176-3187, 2023 Mar 07.
Article in English | MEDLINE | ID: mdl-36790350

ABSTRACT

Cu(II) complexes of cyclen-based ligands CuL1-CuL6 were synthesized and characterized. The corresponding ligands L1-L6 comprise different donor sets including S and O atoms. Whereas cyclen (L1) is commercially available, L2-L6 were synthesized according to protocols available in the literature. Cleavage activity of the complexes towards plasmid DNA was tested in the presence and absence of ascorbate as a reducing agent (oxidative vs. hydrolytic cleavage). As previously shown, the substitution of N donor atoms with hard donor O atoms leads to efficient oxidative nucleases, but dissociation of the complex upon reduction. We thus opted for S substitution (soft donors) to stabilize the reduced Cu(I) species. Increasing the S content, however, leads to species that are difficult to reoxidize in order to ensure efficient oxidative DNA cleavage. We are showing by experimental (cyclic voltammetry) and computational means (DFT) that the rational combination of O and S atoms next to two nitrogen donors within the macrocycle (oxathiacyclen complex CuL6) leads to the stabilization of both redox states. The complex thus exhibits the highest oxidative DNA cleavage activity within this family of cyclen-based Cu(II) complexes - without leaching of the metal ion during reduction.

2.
Chemistry ; 29(14): e202203667, 2023 Mar 07.
Article in English | MEDLINE | ID: mdl-36606721

ABSTRACT

Alzheimer's disease (AD) is an incurable neurodegenerative disease that leads to the progressive and irreversible loss of mental functions. The amyloid beta (Aß) peptide involved in the disease is responsible for the production of damaging reactive oxygen species (ROS) when bound to Cu ions. A therapeutic approach that consists of removing Cu ions from Aß to alter this deleterious interaction is currently being developed. In this context, we report the ability of five different 12-membered thiaazacyclen ligands to capture Cu from Aß and to redox silence it. We propose that the presence of a sole sulfur atom in the ligand increases the rate of Cu capture and removal from Aß, while the kinetic aspect of the chelation was an issue encountered with the 4N parent ligand. The best ligand for removing Cu from Aß and inhibiting the associated ROS production is the 1-thia-4,7,10-triazacyclododecane [3N1S]. Indeed the replacement of more N by S atoms makes the corresponding Cu complexes easier to reduce and thus able to produce ROS on their own. In addition, the ligand with three sulfur atoms has a weaker affinity for CuII than Aß, and is thus unable to remove Cu from CuAß.


Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Humans , Amyloid beta-Peptides/chemistry , Reactive Oxygen Species/metabolism , Ligands , Alzheimer Disease/metabolism , Copper/chemistry
3.
Inorg Chem ; 57(9): 5004-5012, 2018 May 07.
Article in English | MEDLINE | ID: mdl-29683319

ABSTRACT

Many drugs that are applied in anticancer therapy such as the anthracycline doxorubicin contain DNA-intercalating 9,10-anthraquinone (AQ) moieties. When Cu(II) cyclen complexes were functionalized with up to three (2-anthraquinonyl)methyl substituents, they efficiently inhibited DNA and RNA synthesis resulting in high cytotoxicity (selective for cancer cells) accompanied by DNA condensation/aggregation phenomena. Molecular modeling suggests an unusual bisintercalation mode with only one base pair between the two AQ moieties and the metal complex as a linker. A regioisomer, in which the AQ moieties point in directions unfavorable for such an interaction, had a much weaker biological activity. The ligands alone and corresponding Zn(II) complexes (used as redox inert control compounds) also exhibited lower activity.


Subject(s)
Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Copper/chemistry , DNA Replication/drug effects , DNA/biosynthesis , RNA/biosynthesis , Cell Line , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Crystallography, X-Ray , DNA/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Plasmids , RNA/chemistry , Structure-Activity Relationship
4.
Dalton Trans ; 45(26): 10500-4, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27277522

ABSTRACT

A simple approach towards efficient artificial proteases based on the cyclen ligand is presented. We thus achieved an increase of the proteolytic activity of two orders of magnitude when compared to the unsubstituted cyclen complex. Amphiphilic Cu(ii) and Co(iii) complexes cut BSA and myoglobin as model substrates at µM concentrations. MALDI-ToF MS is used to identify the cleavage fragments.


Subject(s)
Cobalt , Coordination Complexes , Copper , Heterocyclic Compounds , A549 Cells , Alkylation , Cell Survival/drug effects , Cobalt/chemistry , Cobalt/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Copper/chemistry , Copper/pharmacology , Cyclams , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Myoglobin/chemistry , Proteolysis , Serum Albumin, Bovine/chemistry
5.
Dalton Trans ; 42(13): 4357-60, 2013 Apr 07.
Article in English | MEDLINE | ID: mdl-23412684

ABSTRACT

The Cu(II) complexes of cyclen and two of its heterosubstituted analogues were shown to be efficient oxidative DNA cleavers. The reactivity strongly depends on the heteroatom inserted into the macrocycle (O > S > N).


Subject(s)
Coordination Complexes/chemistry , Copper/chemistry , DNA/chemistry , Heterocyclic Compounds/chemistry , Crystallography, X-Ray , Cyclams , DNA/metabolism , DNA Cleavage , Molecular Conformation , Oxidation-Reduction , Plasmids/chemistry , Plasmids/metabolism
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