Chemical methods will be developed for the preparation of ten analogs of nicotinamide adenine dinucleotide (NAD) (Class 4) as potential inhibitors of inosine monophosphate dehydrogenase (IMP-dehydrogenase). For the above purpose, methods will be developed to prepare close analogs of nicotinamide riboside (NR) (Classes 1-3) and their 5'-monophosphates (NMN analogs) which will be coupled with AMP. The NAD analogs (Class 4) containing the 2'-deoxy and 3'-deoxy congeners of NR will be synthesized in order to gain information about the role of these OH groups in the formation of coenzyme-enzyme complex. The conformationally restricted analogs of NAD (Class 4) containing NR congeners of Class 2 will be prepared in order to study the specific stereochemical requirements of the cofactor binding site of IMP dehydrogenase. The conformational requirement of NR corresponding NAD analogs will also be studied. Fluorinated NAD analogs (Class 4) containing NR analogs Class 3 will by synthesized in search of developing selective inhibitors of IMP dehydrogenase which are resistant to NAD-glycohydrolases. These analogs might by potentially useful in cancer treatment, especially as radiation sensitizing agents. A few selected IMP-dehydrogenase inhibitors of Class 4 will be converted into their corresponding NAD analogs which contain the pentofuranosyladenine with a fluorine substituent on the C2' position (Class 5) and which contain the metabolically stable methylene- and difluoromethylenediphosphonate moiety (Class 6). Biological, biochemical and chemotherapeutic studies with these synthetic compounds for eventual anticancer drug development are described.
