ABSTRACT
A set of molecules including a majority of metal-N-heterocyclic carbene (NHC) complexes (metal=Ag, Cu, and Au) and azolium salts were evaluated by high-throughput screening of their activity against biofilm formation associated with pathogenic bacteria. The anti-planktonic effects were compared in parallel. Representative biofilm-forming strains of various genera were selected (Listeria, Pseudomonas, Staphylococcus, and Escherichia). All the compounds were tested at 1 mg L(-1) by using the BioFilm Ring Test. An information score (IS, sum of the activities) and an activity score (AS, difference between anti-biofilm and anti-planktonic activity) were determined from normalized experimental values to classify the most active molecules against the panel of bacterial strains. With this method we identified lipophilic Ag(I) and Cu(I) complexes possessing aromatic groups on the NHC ligand as the most efficient at inhibiting biofilm formation.
Subject(s)
Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Coordination Complexes/chemistry , Heterocyclic Compounds/chemistry , Methane/analogs & derivatives , Anti-Bacterial Agents/pharmacology , Biofilms/growth & development , Coordination Complexes/pharmacology , Copper/chemistry , Gold/chemistry , Gram-Negative Bacteria/physiology , Gram-Positive Bacteria/physiology , Methane/chemistry , Microbial Sensitivity Tests , Silver/chemistryABSTRACT
Fourteen silver(I) complexes bearing N-heterocyclic carbene (NHC) ligands were prepared and evaluated for anticancer activity. Some of these were found to exhibit potent antiproliferative activity toward several types of human cancer cell lines, including drug-resistant cell lines, with IC(50) values in the nanomolar range. An initial investigation into the mechanism of cell death induced by this family of silver(I) complexes was carried out. Cell death was shown to result from the activation of apoptosis without involvement of primary necrosis. In HL60 cells, silver-NHCs induce depolarization of the mitochondrial membrane potential (ΔΨ(m)) and likely allow the release of mitochondrial proteins to elicit early apoptosis. This effect is not related to the overproduction of reactive oxygen species (ROS). In addition, apoptosis is not associated with the activation of caspase-3, but is triggered by the translocation of apoptosis-inducing factor (AIF) and caspase-12 from mitochondria and the endoplasmic reticulum, respectively, into the nucleus to promote DNA fragmentation and ultimately cell death. No modification in cell-cycle distribution was observed, indicating that silver-NHCs are not genotoxic. Finally, the use of a fluorescent complex showed that silver-NHCs target mitochondria. Altogether, these results demonstrate that silver-NHCs induce cancer cell death independent of the caspase cascade via the mitochondrial AIF pathway.
Subject(s)
Coordination Complexes , Heterocyclic Compounds , Methane/analogs & derivatives , Silver , Apoptosis/drug effects , Apoptosis Inducing Factor/drug effects , Apoptosis Inducing Factor/metabolism , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Drug Resistance, Neoplasm , Flow Cytometry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Inhibitory Concentration 50 , Methane/chemistry , Methane/pharmacology , Models, Biological , Molecular Structure , Silver/pharmacologyABSTRACT
A simple addition with a large impact: Addition of aromatic amines such as phenanthroline and 4-DMAP (4-dimethylaminopyridine) increases copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) catalytic activity of [CuCl(SIMes)] at a large range of temperatures in such a way that efficient catalysis can safely take place in hydro-alcoholic solvents (see scheme).
Subject(s)
4-Aminopyridine/analogs & derivatives , Copper/chemistry , Nitrogen/chemistry , Phenanthrolines/chemistry , 4-Aminopyridine/chemistry , Alcohols/chemistry , Alkynes/chemistry , Azides/chemistry , Catalysis , Molecular Structure , Solvents , TemperatureSubject(s)
Apoptosis/drug effects , Cell Cycle/drug effects , Copper/chemistry , DNA Cleavage/drug effects , Heterocyclic Compounds/chemistry , Methane/analogs & derivatives , Organometallic Compounds/toxicity , Cell Line, Tumor , Humans , Ligands , Methane/chemistry , Organometallic Compounds/chemistryABSTRACT
New weapons to fight cancer are constantly needed. Among chemotherapeutics, anti-cancer metal-drugs have enjoyed a long and successful history since the discovery of the benchmark cisplatin. Advances in metal-drug discovery have motivated chemists to build plethora of complex structures. Among them, a novel area is emerging. This article presents a survey of the metal-N-Heterocyclic Carbenes (Ag(I), Au(I), Pd(II) and Cu(I)-NHCs) as potential anti-cancer agents. Most of the metal-NHCs considered display higher cytotoxicities than the reference metallo-drug cisplatin. Some of them are even selective for particular cell lines. Their mechanisms of action at the cellular level are further discussed, showing that the nature of the metal is of great importance. All these promising results demonstrate that this approach deserves more attention and work.
Subject(s)
Antineoplastic Agents/pharmacology , Heterocyclic Compounds/pharmacology , Methane/analogs & derivatives , Organometallic Compounds/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Heterocyclic Compounds/chemistry , Humans , Methane/chemistry , Methane/pharmacology , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistryABSTRACT
Electron-poor 6-oxo-1-sulfonyl-1,6-dihydropyridine-3-carboxylates 1b-d undergo cross-Diels-Alder reactions with electron-rich dienes 4a-f under hyperbaric conditions, reacting either as dienophiles to yield normal-electron-demand (NED) cycloadducts 10 and/or 11 or as dienes to give inverse-electron-demand (IED) cycloadducts 12 and/or 13. The latter are converted into 14 and/or 15 through an NED cycloaddition with a second equivalent of electron-rich diene. Acyclic dienes display a propensity to yield NED products, whereas cyclic dienes tend to favor IED cycloadducts. High-pressure activation compares favorably with thermal or microwave activation in terms of both yields and suppression of the transformation of 1 into unreactive pyridines 3. Whereas the Cope rearrangement from IED to NED occurs under thermal conditions, no evidence of its involvement under high pressure could be detected. These and other data point to similar activation energies for the NED and IED processes under these conditions.
