ABSTRACT
Neurodegenerative diseases are often characterized by the formation of aggregates of amyloidogenic peptides and proteins, facilitating the formation of neurofibrillary plaques. In this study, we investigate a series of Ru-complexes sharing three-legged piano-stool structures based on the arene ring and glucosylated carbene ligands. The ability of these complexes to bind amyloid His-peptides was evaluated by ESI-MS, and their effects on the aggregation process were investigated through ThT and Tyr fluorescence emission. The complexes were demonstrated to bind the amyloidogenic peptides even with different mechanisms and kinetics depending on the chemical nature of the ligands around the Ru(II) ion. TEM analysis detected the disaggregation of typical fibers caused by the presence of Ru-compounds. Overall, our results show that the Ru-complexes can modulate the aggregation of His-amyloids and can be conceived as good lead compounds in the field of novel anti-aggregating agents in neurodegeneration.
Subject(s)
Antineoplastic Agents , Coordination Complexes , Ruthenium , Molecular Structure , Antineoplastic Agents/chemistry , Ruthenium/pharmacology , Ruthenium/chemistry , Histidine , Ligands , Peptides , Amyloidogenic Proteins , Coordination Complexes/chemistryABSTRACT
This study describes new platinum(II) cationic five-coordinate complexes (1-R,R') of the formula [PtR(NHC)(dmphen)(ethene)]CF3SO3 (dmphen = 2,9-dimethyl-1,10-phenanthroline), containing in their axial positions an alkyl group R (methyl or octyl) and an imidazole-based NHC-carbene ligand with a substituent R' of variable length (methyl or octyl) on one nitrogen atom. The Pt-carbene bond is stable both in DMSO and in aqueous solvents. In DMSO, a gradual substitution of dmphen and ethene is observed, with the formation of a square planar solvated species. Octanol/water partitioning studies have revealed the order of hydrophobicity of the complexes (1-Oct,Me > 1-Oct,Oct > 1-Me,Oct > 1-Me,Me). Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and able to activate the apoptotic pathway. The reactivity of 1-Me,Me with DNA and protein model systems was also studied using UV-vis absorption spectroscopy, fluorescence, and X-ray crystallography. The compound binds DNA and interacts in various ways with the model protein lysozyme. Remarkably, structural data revealed that the complex can bind lysozyme via non-covalent interactions, retaining its five-coordinate geometry.
Subject(s)
Antineoplastic Agents , Muramidase , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Crystallography, X-Ray , Dimethyl Sulfoxide , DNA , Hydrophobic and Hydrophilic Interactions , Platinum Compounds/chemistry , Platinum Compounds/pharmacologyABSTRACT
New neutral carbene complexes of gold(I) [Au(Im-Me)X] (X = Cl, Au1; X = Br, Au2; X = I, Au3) have been synthesized and fully characterized by different techniques, including NMR and UV-vis absorption spectroscopy and single crystal X-ray diffraction. The carbene ligand Im-Me is decorated with a glucoside fragment via a triazole linker, obtainable through a click chemistry reaction. The compounds retain the Au-NHC fragment in aqueous solvents, and an equilibrium between the neutral halo- and the cationic di-carbene form [Au(Im-Me)2]+ is observed, whose extent follows the trend Au1 < Au2 < Au3. Cytotoxicity studies on two cancer and two non-tumorigenic cell lines reflect the solution behavior, as a certain difference among the complexes was disclosed, with the iodo complex Au3 being more active and selective. The compounds interact with both DNA and protein model systems. The X-ray structure of the adduct formed upon the reaction of Au1 with bovine pancreatic ribonuclease (RNase A) reveals Au binding at the side chain of His105 of both protein molecules A and B of the asymmetric unit. The binding of gold atoms at both the nitrogen atoms of the imidazole ring of His15 and at the N-terminal tail has been found in the adduct formed with hen egg white lysozyme.
Subject(s)
DNA , Gold , Animals , Cattle , Glycoconjugates/pharmacology , Gold/chemistry , Ligands , Methane/analogs & derivatives , Models, MolecularABSTRACT
This article describes the synthesis, characterization, and biological activity of novel square-planar cationic platinum(II) complexes containing glucoconjugated triazole ligands and a comparison with the results obtained from the corresponding five-coordinate complexes bearing the same triazole ligands. Stability in solution, reactivity with DNA and small molecules of the new compounds were evaluated by NMR, fluorescence, and UV-vis absorption spectroscopy, together with their cytotoxic action against pairs of immortalized and tumorigenic cell lines. The results show that the square-planar species exhibit greater stability than the corresponding five-coordinate ones. Furthermore, although the square-planar complexes are less cytotoxic than the latter ones, they exhibit a certain selectivity. These results simultaneously demonstrate that overall stability is a fundamental prerequisite for preserving the performance of the agents and that coordinative saturation constitutes a point in favor of their biological action.
Subject(s)
Antineoplastic Agents/chemical synthesis , Glucose/chemistry , Organoplatinum Compounds/chemical synthesis , Triazoles/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Ligands , MCF-7 Cells , Molecular Structure , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Proton Magnetic Resonance Spectroscopy , RatsABSTRACT
The design of novel metal complexes with N-heterocyclic carbene (NHC) ligands that display biological activity is an active research field in organometallic chemistry. One of the possible approaches consists of the use of NHC ligands functionalized with a carbohydrate moiety. Two novel Au(I)-Au(I) dinuclear complexes were synthesized; they present a neutral structure with one bridging diNHC ligand, having one or both heterocyclic rings decorated with a carbohydrate functionality. With the symmetric diNHC ligand, the dicationic dinuclear complex bearing two bridging diNHC ligands was also synthesized. The study was completed by analyzing the antiproliferative properties of these complexes, which were compared to the activity displayed by similar mononuclear Au(I) complexes and by the analogous bimetallic Au(I)-Au(I) complex not functionalized with carbohydrates.
Subject(s)
Antineoplastic Agents , Cell Proliferation/drug effects , Gold/chemistry , Heterocyclic Compounds , Neoplasms/drug therapy , Organogold Compounds , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , BALB 3T3 Cells , Cell Line, Tumor , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Mice , Neoplasms/metabolism , Neoplasms/pathology , Organogold Compounds/chemical synthesis , Organogold Compounds/chemistry , Organogold Compounds/pharmacologyABSTRACT
Octahedral Pt(IV) complexes (2Pt-R) containing a glycoconjugate carbene ligand were prepared and fully characterized. These complexes are structural analogues to the trigonal bipyramidal Pt(II) species (1Pt-R) recently described. Thus, an unprecedented direct comparison between the biological properties of Pt compounds with different oxidation states and almost indistinguishable structural features was performed. The stability profile of the novel Pt(IV) compounds in reference solvents was determined and compared to that of the analogous Pt(II) complexes. The uptake and antiproliferative activities of 2Pt-R and 1Pt-R were evaluated on the same panel of cell lines. DNA and protein binding properties were assessed using human serum albumin, the model protein hen egg white lysozyme, and double stranded DNA model systems by a variety of experimental techniques, including UV-vis absorption spectroscopy, fluorescence, circular dichroism, and electrospray ionization mass spectrometry. Although the compounds present similar structures, their in-solution stability, cellular uptake, and DNA binding properties are diverse. These differences may represent the basis of their different cytotoxicity and biological activity.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Glycoconjugates/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cattle , Cell Line, Tumor , Chickens , Coordination Complexes/chemical synthesis , Coordination Complexes/metabolism , DNA/metabolism , Drug Screening Assays, Antitumor , Glycoconjugates/chemical synthesis , Glycoconjugates/metabolism , Humans , Ligands , Mice , Molecular Structure , Muramidase/metabolism , Platinum/chemistry , Protein Binding , Serum Albumin, Human/metabolismABSTRACT
New five-coordinate Pt(ii) complexes containing a glycosylated carbene fragment were synthesized. A member of this class shows very high in vitro cytotoxicity and an exceptional selectivity toward malignant cells. The complex lacking the sugary portion fails in the recognition of cancer cells. The results support the use of glycosylation in the design of carbene Pt-based anticancer agents.
