A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones has been developed. This new method, based on microwave heating at 220 degrees C for 600 seconds in N-methyl pyrrolidone (NMP), proved to be practical and very efficient, resulting in decarboxylated 2-pyridones in near-quantitative yields. The decarboxylated products and the intermediate 2-pyridones in the form of carboxylic acid methyl esters and carboxylic acids were screened for their effect on Abeta-peptide aggregation. Two out of the 21 2-pyridones described in this study inhibited amyloid formation of the Alzheimer Abeta(1-40) peptide. The effect was seen even at a 4 : 1 ratio of 2-pyridone and monomeric Abeta-peptide.

The formation of N,N-dimethylcarbamoyl chloride (DMCC) in Vilsmeier reactions (VRs) and the hydrolysis of DMCC during aqueous workup were investigated. The amount of DMCC formed was dependent on the chlorination reagent. The activity order was found to be: thionyl chloride > oxalyl chloride > phosphorus oxychloride. The concentrations of DMCC found in the tested reactions were normally at a level of 0-20 ppm. In the presence of a base the level was higher. DMCC hydrolyzed quickly under aqueous workup conditions. No more than 3 ppm of DMCC could be detected in the product after aqueous workup of the tested VR. Our results clearly indicate that by following the described procedure for VR it is perfectly safe from the health risk point of view to operate this chemistry when preparing compounds for pharmaceutical use. A very useful analytical procedure for detection and quantification of trace amounts of DMCC formed in the VR was developed. The method was based on derivatization of DMCC with ethanol to form ethyl N,N-dimethylcarbamate and analysis by GC coupled to a mass spectrometer in selected ion monitoring mode. The analytical method was selective and showed very good linearity. The limit of detection (LOD) and limit of quantification (LOQ) of DMCC using standard addition analysis with real Vilsmeier reaction matrices were determined to be LOD ) 0.2 ppm and LOQ ) 0.7 ppm.

Decarboxylation O 0296Microwave-Assisted Decarboxylation of Bicyclic 2-Pyridone Scaffolds and Identification of Aβ-Peptide Aggregation Inhibitors. -The lithium salts of pyridone derivatives (Ia) and (Ib) are found to inhibit the amyloid formation of the Alzheimer Aβ(1-40) peptide. -(AABERG, V.; NORMAN, F.; CHORELL, E.; WESTERMARK, A.; OLOFSSON, A.; SAUER-ERIKSSON, A. E.; ALMQUIST*, F.; Org. Biomol. Chem. 3 (2005) 15, 2817-2823; Dep. Chem., Org. Chem., Umea Univ., S-901 87 Umea, Swed.; Eng.) -Nuesgen 49-055

A new fluorescent biarsenical peptide labeling probe was synthesized and labeled with the radioactive isotopes 11 C and 18 F. The utility of this probe was demonstrated by installing each of these isotopes into a melanocortin 1 receptor (MC1R) binding peptide, which targets melanoma tumors. Its applicability was further showcased by subsequent in vitro imaging in cells as well as in vivo imaging in melanoma xenograft mice by fluorescence and positron emission tomography.