Microwaves and Heterocycles: New Methodology and Chemotherapeutic Opportunities
Mark C. Bagley
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, Wales, UK
Email Bagleymc@cf.ac.uk; Tel 029 2087 4029; Fax 029 2087 4030

Abstract
Microwave irradiation accelerates a range of transformations in heterocyclic chemistry, with shorter reaction times, improved yields and enhanced product purity. We have applied these techniques in a chemical genetics approach to understand the biochemical basis of accelerated ageing in Werner syndrome (WS) so we can intervene in the pathology of this disease. The use of microwave heating has delivered a library of complementary compounds to understand the role of cell signalling in the pathology of WS. P38a mitogen activated protein kinase inhibitors, originally developed by the pharmaceutical industry for the treatment of inflammatory disorders, and a downstream inhibitor (MK2) of this signal transduction cascade have been prepared and tested in Werner syndrome cells. Microwave irradiation was found to improve routes to the Vertex compound VX-745, Boehringer-Ingelheim's BIRB 796, MK2 inhibitors from Pfizer and the Roche compound RO3201195. Furthermore, when some of these chemical inhibitors were added to Werner syndrome fibroblasts, their growth rate and cell morphology was restored. This opens the opportunity for using chemotherapeutic treatments for inflammatory conditions to combat rapid ageing in Werner syndrome patients.