This program is aimed at the synthesis of several new types of nucleoside analogs that are expected to be useful as antitumor agents and enzyme inhibitors, as probes of the conformational factors involved in the binding of pyrimidines to some of the enzymes of nucleic acid metabolism, or as antiprotozoal agents. Specifically, four classes of target nucleosides are proposed. Classes A and B which contain uridines substituted at C-6 with an alkene group and 6',6-cyclonucleosides bearing a 6',6-double bond, are intended to amplify and extend our ongoing work with 6- vinyluracil and related compounds. Like the free bases, the nucleosides are expected to function as alkylating agents, but their increased solubility and potential for altered distribution may result in improved antitumor activity. Target classes C and D are new to the program but they are related to ongoing work in that the syntheses to be used are extensions of methods developed for earlier target compounds. The cyclonucleosides of class C can be regarded as conformationally-restricted analogs of ordinary nucleosides, and they are particularly interesting because the extended bridge endows them with considerable flexibility. The interactions of compounds of type C with pyrimidine-requiring enzymes could furnish useful information on the range of substrate conformations acceptable to the particular enzyme being studied. Initial studies will be with uridine phosphorylase, in collaboration with Dr. M. el Kouni at Brown University. Target compound D - a furopyrimidine C-nucleoside - has recently been found to be very active against Trypanosoma gambiense. Since the compound is difficult to prepare, we intend to develop a new approach that uses methods we have developed in previous work with 5-hydroxypyrimidines and pyrimidine 5',6- cyclonucleosides. In-house studies will be performed to assess biological activities of target compounds. The Laboratory of Experimental Antitumor Testing (Drs. B. Mehta and F. Schmid) will test for activity against mouse and human tumor cell lines growing in culture, and active compounds will be further evaluated for in vivo activity in mice bearing leukemias or solid tumors.
|Schwartz, E L; Baptiste, N; O'Connor, C J et al. (1994) Potentiation of the antitumor activity of 5-fluorouracil in colon carcinoma cells by the combination of interferon and deoxyribonucleosides results from complementary effects on thymidine phosphorylase. Cancer Res 54:1472-8|
|el Kouni, M H; Naguib, F N; Chu, S H et al. (1988) Effect of the N-glycosidic bond conformation and modifications in the pentose moiety on the binding of nucleoside ligands to uridine phosphorylase. Mol Pharmacol 34:104-10|