An efficient route to xanthine based A(2A) adenosine receptor antagonists and functional derivatives.

A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family of A(2A) adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented including a pro-drug variant, and application to related image contrast agents developed.

Designed DNA probes from the neocarzinostatin family: impact of glycosyl linkage stereochemistry on bulge base binding.

Bulged sites in DNA and RNA have become targets for rational drug design due to their suspected involvement in a number of key biomolecular processes. A lead compound, derived from the enediyne natural product NCS-chrom has been used to inform chemical synthesis of a family of designed probes of DNA bulges, one of which shows 80 nM affinity for a two base bulged target. Key contributors to binding of these spirocyclic compounds have been studied in order to correlate affinity and specificity with structural features. Herein, we demonstrate that the glycosyl linkage stereochemistry of the pendant aminofucosyl group plays a pivotal role in binding, and coupled with insight obtained with various bulged targets, will allow rational design of second generation ligands.

Synthesis, functionalization and photo-Bergman chemistry of enediyne bioconjugates.

Methodology is outlined for the chemical synthesis of versatile photo-Bergman enediyne building blocks and their conjugates. Routes to both mono and bis conjugated enediyne templates are detailed together with representative examples of their bioconjugates, nanoconjugates, PEG derivatives and water soluble salts. The immunocompetence of antibody conjugates is retained, and application in the form of reagents for photodynamic therapy (PDT) advanced.

Microwave accelerated labeling methods in the synthesis of radioligands for positron emission tomography imaging.

Nuclear imaging using positron emission tomography [PET] is a powerful technique with clinical applications which include oncology, cardiovascular disease and CNS disorders. Conventional chemical syntheses of the short half-life radionuclides used in the process however imposes numerous limitations on scope of available ligands. By utilizing microwave assisted synthesis methods many of these limitations can be overcome, paving the way for the design of diverse families of agents with defined cellular targets. This review will survey recent developments in the field with emphasis on the period 2006-2011. Positron emission tomography [PET] has become one of the most powerful in vivo imaging modalities, capable of delivering mm3 resolution of radiotracer distribution and metabolism [1]. When combined with anatomic imaging methods (MRI, CT) co-registered multimode images offer the potential to track metabolic and physiologic events in diseased states and guide and accelerate clinical trials of investigational new drugs. Also, this same methodology can be used to evaluate first pass pharmacokinetics/pharmacodynamics in early stage drug discovery. Though powerful as a technique only a limited number of drugs have seen clinical use and to date only one drug 2-fluoro-deoxy-D-glucose (FDG) has received FDA approval [2]. One of the drawbacks of PET imaging is the need for tracers labeled with an appropriate nuclide and the half-lives of these agents places special constraints on the chemical synthesis. Among the most popular are 11C (t½ =20.4 min) and 18F (t ½ =109.8 min) labeled compounds and this has resulted in a resurgence of interest in practical application of their chemistries [3,4]. This review will focus on microwave mediated methods of acceleration of organic reactions used for the production of labeled PET image contrast agents, with emphasis on the five year period 2006 to 2011.