Synthetic approach to a transglycosidically tethered inosine 5'-monophosphate

CHED 327

Michael P. Groziak, michael.groziak@csueastbay.edu and Tara Arends, tara_arends@yahoo.com. Department of Chemistry & Biochemistry, California State University East Bay, 25800 Carlos Bee Blvd., Hayward, CA 94542-3087
Inhibition of inosine monophosphate dehydrogenase (IMPDH) can play an important role in antileukemic and immunosuppressive therapies. By protein crystallography, it is known that this enzyme binds 5'-IMP as its lower energy anti glycosidic rotamer. To date, the first 8 steps along an 11-step synthetic route towards an 8,5'-transglycosidically tethered version of 5'-IMP locked in an anti conformation have been accomplished, giving an 8,5'-methyleneoxo tethered version of inosine as a cyclic hemiacetal. Details of the multi-step nucleoside synthesis and progress toward the final tethered IMP target will be presented. Ultimately, the target 5'-IMP analog diastereomers will be tested separately in an IMPDH enzyme assay with the goal of highlighting a new platform for constructing even more effective antileukemic chemotherapeutics.