ABSTRACT
Spatially addressable combinatorial libraries were synthesized by solution phase chemistry and screened for binding to human serum albumin. Members of arylidene diamide libraries were among the best hits found, having submicromolar binding affinities. The results were analyzed by the frequency with which particular substituents appeared among the most potent compounds. After immobilization of the ligands either through the oxazolone or the amine substituent, characterization by surface plasmon resonance showed that ibuprofen affected the binding kinetics, but phenylbutazone did not. It is therefore likely that these compounds bind to Site 2 in sub domain IIIA of human serum albumin (HSA).
Subject(s)
Chromatography, Affinity/methods , Combinatorial Chemistry Techniques , Ligands , Serum Albumin/metabolism , Binding Sites/drug effects , Binding, Competitive , Cross-Linking Reagents , High-Throughput Screening Assays , Humans , Ibuprofen/pharmacology , Kinetics , Oxazolone/chemistry , Phenylbutazone/pharmacology , Protein Binding , Protein Structure, Tertiary , Serum Albumin/chemistry , Surface Plasmon ResonanceABSTRACT
Scope and limitations of the base-free oxidative Heck reaction with arylboronic acids have been explored. Under our conditions, the dmphen-palladium(II)-catalyzed arylation proceeded with air or p-benzoquinone as reoxidants of palladium(0). We found that ambient temperature and mild aerobic conditions allow for the use of substrates sensitive to palladium(II)-catalyzed oxidation. Oxidative Heck couplings, employing different arylboronic acids, were smoothly and regioselectively conducted with both electron-rich and electron-poor olefins, providing high yields even with disubstituted butyl methacrylate, sensitive acrolein, and a vinylboronate ester. Controlled microwave processing was used to reduce reaction times from hours to minutes both in small scale and in 50 mmol scale batch processes.
Subject(s)
Acrylates/chemistry , Benzene Derivatives/chemistry , Boronic Acids/chemistry , Chemistry, Organic/methods , Hot Temperature , Microwaves , Palladium/chemistry , Aerobiosis , Catalysis , Oxidation-Reduction , TemperatureABSTRACT
Microwave-assisted organic synthesis has revolutionized organic synthesis. Small molecules can be built in a fraction of the time required by classical thermal methods. As a result, this technique has rapidly gained acceptance as a valuable tool for accelerating drug discovery and development processes. This article outlines the basic principles behind microwave technology and summarizes recent trends and areas in drug discovery where this technology has made an impact.
Subject(s)
Drug Design , Microwaves , Pharmaceutical Preparations/chemical synthesis , Chemistry, Organic/instrumentation , Chemistry, Organic/methodsABSTRACT
A series of substituted acetophenones, paraformaldehyde, and symmetrical dialkylamines were used in microwave enhanced Mannich reactions. Appropriate reaction conditions in terms of choice of solvent, reaction temperature, and reaction time were studied to allow a fast and reproducible production of Mannich bases. Both small (2 mmol) and large scale reactions (40 mmol) were performed successfully, providing a series of substituted Mannich bases in moderate to high yields and high purity.
