The objective of this proposal is to synthesize a number of nucleosides which have a high potential for use as chemotherapeutics in neoplastic diseases. The proposed nucleosides are designed to be substrates and inhibitors of specific enzymes, such as, orotidine 5'-monophosphate decarboxylase of the de novo pyrimidine pathway and IMP dehydrogenase, the rate limiting enzyme of the de novo GTP biosynthetic pathway. The nucleosides proposed in this study are isosteric with naturally occurring nucleosides and are expected to provide a new class of nucleoside oncolytic agents. Indeed, the proposed nucleosides, due to the carbon- carbon linkage between the carbohydrate and heterocyclic moieties, and the stability toward both chemical hydrolytic and enzymatic phosphorylytic cleavage that this type of glycosidic bound imparts of the molecule, may be superior agents in comparison to the analogous N-nucleosides. The proposed nucleosides an excellent alternative as a potential inhibitor of orotidine-5'-monophosphate decarboxylase (EC 4.1.1.23) which would not be expected to be degraded by cleavage of the glycosidic bond. The second objective of this proposal is to prepare isosteric analogues of nicotinamide nucleoside for oncolytic evaluation. The target enzyme would be IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of the de novo GTP biosynthetic pathway. It is proposed that the nucleosides of objective 2 are excellent candidates to be converted into the corresponding NAD analogues and inhibit IMP dehydrogenase. In addition to the above targeted enzyme-specific nucleosides we propose to fully explore the potential of this new class of nucleosides. The synthesis of 2'- deoxynucleosides are proposed since they may act as inhibitors of DNA polymerase. The compounds developed on this project would be evaluated in an in vitro screen against L-12190, H.Ep. 2 UMSCC-10A and UMSCC-38 cell lines by Dr. L. L. Wotring (no funds requested), as well as the screen of N.C.I.
| Walker 2nd, J A; Liu, W; Wise, D S et al. (1998) Synthesis and antiviral evaluation of certain novel pyrazinoic acid C-nucleosides. J Med Chem 41:1236-41 |
