ABSTRACT
The coordination-driven synthesis of a rhomboid cavitand composed of two different Bodipys and its inclusion complex with 1,3,6,8-tetrasulfopyrene via ionic self-assembly was established by X-ray crystallography. Highly efficient and unidirectional intra-host and guest-to-host energy transfer was demonstrated by femtosecond fluorescence spectroscopy.
ABSTRACT
Prion diseases are fatal, neurodegenerative diseases characterized by the structural conversion of the normal, cellular prion protein, PrP (C) into an abnormally structured, aggregated and partially protease-resistant isoform, termed PrP (Sc) . Although substantial research has been directed toward development of therapeutics targeting prions, there is still no curative treatment for the disease. Benzoxazines are bicyclic heterocyclic compounds possessing several pharmaceutically important properties, including neuroprotection and reactive oxygen species scavenging. In an effort to identify novel inhibitors of prion formation, several 5,7,8-trimethyl-1,4-benzoxazine derivatives were evaluated in vitro for their effectiveness on the expression levels of normal PrP (C) and its conversion to the abnormal isoforms of PrP (Sc) in a scrapie-infected cell culture model. The most potent compound was 2-(4-methoxyphenyl)-5,7,8-trimethyl-3,4-dihydro-2H-1,4-benzoxazine, with a diminishing effect on the formation of PrP (Sc) , thus establishing a class of compounds with a promising therapeutic use against prion diseases.
Subject(s)
Benzoxazines/pharmacology , PrPSc Proteins/antagonists & inhibitors , PrPSc Proteins/metabolism , Scrapie/metabolism , Animals , Benzoxazines/chemistry , Cell Line, Tumor , Mice , PrPC Proteins/metabolismABSTRACT
The Escherichia coli AtoSC two component system;upon acetoacetate induction;regulates the expression of the atoDAEB operon;through HisâAsp phopshotransfer;thus modulating important cellular processes. In this report the effect of seven 5,7,8-trimethyl-1,4-benzoxazine derivatives on the regulation of the E. coli AtoSC system was studied. The new compounds were tested for their effectiveness on the expression of the atoC and the regulated atoDAEB operon. The non-substituted 5,7,8-trimethyl-1,4-benzoxazine (4a), was the most potent inducer on atoC transcription;resulting in accumulation of AtoC protein. The induction of atoC by 4a was specific;since no effect was observed on the other genes of the system (atoS and atoDAEB). Moreover;compound 4a was shown to significantly up-regulate the in vitro kinase activity of the histidine kinase AtoS without altering the protein levels in the cell. Interestingly;this compound appeared to modulate the acetoacetate-mediated induction of the atoDAEB promoter by the AtoSC system. These data provide the first evidence for a differential modulator role of 5,7,8-trimethyl-1,4-benzoxazine;on the AtoSC two component system mediated signaling.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzoxazines/chemical synthesis , Escherichia coli Proteins/drug effects , Escherichia coli/drug effects , Protein Kinases/drug effects , Acetoacetates/chemical synthesis , Acetoacetates/chemistry , Acetoacetates/metabolism , Acetoacetates/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Benzoxazines/chemistry , Benzoxazines/pharmacology , Dose-Response Relationship, Drug , Drug Design , Escherichia coli/genetics , Escherichia coli/metabolism , Escherichia coli Proteins/genetics , Escherichia coli Proteins/metabolism , Gene Expression Regulation/drug effects , Molecular Targeted Therapy , Operon/drug effects , Protein Kinases/genetics , Protein Kinases/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Structure-Activity Relationship , Transcription, Genetic/drug effects , Transcriptional Activation/drug effects , Up-Regulation/drug effectsABSTRACT
6-Hydroxy-5,7,8-trimethyl-benzopyran derivatives and 5,7,8-trimethyl-1,4-benzoxazine analogues substituted by the lidocaine pharmacophore aminoamide functionality at C4 or N4, respectively, were synthesized and evaluated against arrhythmias associated with ischemia-reperfusion injury. The antiarrhythmic effect of substitutents at positions C2 and C6 was examined. Six out of the 11 new derivatives, exhibited arrhythmia scores 1.0-1.3 versus the control (4.5 +/- 1.2), which was also reflected to the % premature beats (0.5-3.9), control (13.7 +/- 3.6). Selected compounds were further studied by a conventional microelectrode method. 2-Diethylamino-1-(5,7,8-trimethyl-2-phenyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethanone (50) and the trolox-inspired 4-(2-diethylamino-acetyl)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester (62) suppress reperfusion arrhythmias and reduce malondialdehyde (MDA) content, leading to a fast recovery of the heart after ischemia-reperfusion. They exhibit combined class IB and class III antiarrhythmic properties, which constitutes them as promising compounds for further studies because, due to their multichannel "amiodarone like" effect, less proarrhythmic complications can be expected.
Subject(s)
Amides/chemical synthesis , Anti-Arrhythmia Agents/chemical synthesis , Benzopyrans/chemical synthesis , Benzoxazines/chemical synthesis , Myocardial Reperfusion Injury/drug therapy , Action Potentials , Amides/chemistry , Amides/pharmacology , Animals , Anti-Arrhythmia Agents/chemistry , Anti-Arrhythmia Agents/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Benzopyrans/chemistry , Benzopyrans/pharmacology , Benzoxazines/chemistry , Benzoxazines/pharmacology , Female , Heart/drug effects , Heart/physiology , Lipid Peroxidation/drug effects , Male , Papillary Muscles , Rabbits , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Unsymmetrical functionalised cyanine dyes, covering the whole colour range, were readily synthesised (in 100 mg amounts) by a combination of microwave and solid-phase methodologies.