ABSTRACT
Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB4 ) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one-pot Wittig olefination and base-mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner-Wadsworth-Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto-desilylation protocol furnished LXB4 in 25 % overall yield in just 10â steps. For the first time, LXB4 has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB4 showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB4 , enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.
Subject(s)
Lipoxins , Neuroinflammatory Diseases , Eicosanoids , Humans , Lipoxins/metabolismABSTRACT
In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.
Subject(s)
Indoles/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Purinergic P2 Receptor Antagonists/pharmacology , Pyridazines/pharmacology , Receptors, Purinergic P2Y12/metabolism , Acute Coronary Syndrome/prevention & control , Adenosine Diphosphate/pharmacology , Administration, Oral , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Humans , Indoles/chemical synthesis , Indoles/metabolism , Injections, Intravenous , Male , Models, Chemical , Molecular Structure , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/metabolism , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/metabolism , Pyridazines/chemical synthesis , Pyridazines/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2Y12/genetics , Thrombosis/prevention & controlABSTRACT
Fourteen different ligands have been synthesized with two covalently linked 8-hydroxyquinoline motifs that favor metal complexation. These bis-chelators include different bridges at the C2 positions and different substituents to modulate their physicochemical properties. They can form metal complexes in a ratio of one ligand per metal ion with Cu II and Zn II, two metal ions involved in the formation of amyloid aggregates of the toxic Abeta-peptides in the Alzheimer disease. The apparent affinity of all bis-8-hydroxyquinoline ligands for Cu II and Zn II are similar with logK Cu II approximately 16 and logK Zn II approximately 13 and are 10,000 times more efficient than for the corresponding 8-hydroxyquinoline monomers. Their strong chelating capacities allow them to inhibit more efficiently than the corresponding monomers the precipitation of Abeta-peptides induced by Cu II and Zn II and also to inhibit the toxic formation of H2O2 due to copper complexes of Abeta. The best results were obtained with a one-atom linker between the two quinoline units. X-ray analyses of single-crystals of Cu II, Zn II or Ni II complexes of 2,2'-(2,2-propanediyl)-bis(8-hydroxyquinoline), including a one-atom linker, showed that all heteroatoms of the bis-8-hydroxyquinoline ligand chelate the same metal ion in a distorted square-planar geometry. The Cu II and Zn II complexes include a fifth axial ligand and are pentacoordinated.
Subject(s)
Alzheimer Disease , Chelating Agents/chemical synthesis , Organometallic Compounds/chemical synthesis , Oxyquinoline/chemistry , Polymers/chemistry , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/drug effects , Chelating Agents/chemistry , Chelating Agents/pharmacology , Copper/chemistry , Crystallography, X-Ray , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/chemical synthesis , Hydrogen Peroxide/chemistry , Hydrophobic and Hydrophilic Interactions , Ligands , Models, Molecular , Molecular Structure , Nickel/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Peptide Fragments/chemistry , Peptide Fragments/drug effects , Zinc/chemistryABSTRACT
The design and synthesis of new heterodinuclear DNA-targeting agents are described. The abilities of cisplatin and Cu(3-Clip-Phen) [Cu(1-(1,10-phenanthrolin-3-yloxy)-3-(1,10-phenanthrolin-8-yloxy)propan-2-amine)Cl2], an artificial DNA-cleaving agent, have been combined through their "covalent coupling". This strategy has led to bifunctional complexes that are able to cleave the DNA in a double-stranded fashion in contrast to Cu(3-Clip-Phen) alone and have promising cytotoxicities compared to cisplatin in several cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cisplatin/analogs & derivatives , Cisplatin/chemical synthesis , DNA Cleavage , Organometallic Compounds/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cisplatin/pharmacology , Drug Screening Assays, Antitumor , Humans , Organometallic Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
Mechanistic investigations on the oxidative coupling of 2,6-dimethylphenol have led to the development of a selective and efficient procedure to prepare 3,5,3',5'-tetramethyl-biphenyl-4,4'-diol, via a C-C coupling, mediated by a hypervalent form of iodine, i.e. (diacetoxyiodo)benzene and for which a mechanism is proposed.
Subject(s)
Chelating Agents/chemical synthesis , Chelating Agents/therapeutic use , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/therapeutic use , Metals/chemistry , Neurodegenerative Diseases/drug therapy , Alzheimer Disease/drug therapy , Animals , Chelating Agents/chemistry , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Ions/chemistry , Ligands , Macrocyclic Compounds/chemistry , Mice , Mice, Transgenic , Molecular Structure , Phenanthrolines/chemical synthesis , Phenanthrolines/therapeutic use , Plaque, Amyloid/drug effectsABSTRACT
A copper(II) neocuproine system has been developed for the efficient and very selective 1,6-addition of a nucleophile to the para-methyl group of 2,4,6-trimethylphenol. Crystallographic and spectroscopic data point towards the involvement of a micro-methoxo-micro-phenoxo-bridged copper species which appears to generate a highly reactive quinone methide intermediate that can be attacked by a nucleophilic reagent.
Subject(s)
Copper/chemistry , Cresols/chemistry , Crystallography, X-Ray , Methanol/chemistry , Methylation , Models, Molecular , Molecular Structure , Oxidation-Reduction , Phenols/chemistry , Solutions , Spectrum AnalysisSubject(s)
Carbon/chemistry , Copper/chemistry , Hydrogen/chemistry , Hydrogen Bonding , Oxidation-ReductionABSTRACT
The cytostatic activities of a series of twelve 1,10-phenanthroline (Phen) derivatives and of their copper complexes were studied on L1210 murine leukemia cells. Large increases in the biological activity were observed for compounds of the 3-Clip-Phen series, in which two Phen moieties were bridged at their C3 positions by an alkoxy linker, the 3-pentyl-Clip-Phen derivative showing an IC(50) value of 130 nM while Phen shows an IC(50) value of 2500 nM under the same conditions. IC(50) values seemed to be modulated not only by the position, the nature, and the length of the linker of Clip-Phen but also by hydrophobicity. Since copper complexes of Phen are chemical nucleases and nucleic acids are thus a potential target for these compounds, the corresponding copper complexes were also studied. Copper complexation of the 3-Clip-Phen ligands did not increase their biological activities. Attempts to vectorize 3-Clip-Phen derivatives with a DNA binder such as spermine or with a cell-penetration peptide failed to increase their biological activity relative to the original 3-Clip-Phen series.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Phenanthrolines/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Copper/chemistry , Inhibitory Concentration 50 , Leukemia L1210/pathology , Mice , Phenanthrolines/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of the new polynucleating ligand 1,3-bis-(3-oxo-3-(2-hydroxyphenyl)-propionyl)-benzene (H4L) is reported along with the preparation, structure and properties of its dinuclear complexes [Cu(2)(H(2)L)(2)(py)(2)](1), [Ni(2)(H(2)L)(2)(py)(4)](2), [Mn(2)(H(2)L)(2)(dmf)(4)](3), [Co(2)(H(2)L)(2)(dmf)(4)](4) and [Co(2)(H(2)L)(2)(MeOH)(4)](5), respectively. In complexes 1 to 5, the polydentate ligand is in its bis-deprotonated form, chelating the metals through its [small beta]-diketonate moieties. Magnetic measurements show that the metals within these molecules are maintained almost mutually independent.
ABSTRACT
To increase the DNA cleavage activity and the cell delivery of the bis(phenanthroline) DNA cleaver "3-Clip-Phen", conjugates between 3-Clip-Phen and the intercalators acridine and 6-chloro-2-methoxyacridine, through amino acid linkers of various length, were prepared. After complexation with CuCl(2), the ability of these conjugates to cleave phiX 174 DNA in the presence of a reductant and air was compared. The results indicated that (i) the coupling of 3-Clip-Phen to an acridine derivative increased the DNA cleavage efficiency of the copper complexes, (ii) the acridine derivatives were more active than 6-chloro-2-methoxyacridine derivatives, (iii) the linker length influenced cleavage efficiency, the highest DNA cleavage activity being obtained for an aminocaproic spacer.