The overall goal of this project is concerned with the design of new inhibitors of the enzyme uridine phosphorylase. As will be seen in section B, uridine phosphorylase plays an important role in cancer chemotherapy, and inhibitors of this enzyme have a potential role to play as adjuvant agents in the chemotherapy of cancer with fluoropyrimidines. The enzyme is also unusual in that it is known to bind nucleosides in the syn conformation. In order to exploit this conformational factor, we propose to synthesize the new cyclonucleosides 1-1 - 1-3 shown in figure 1. These compounds, while they are expected to retain some flexibility, are restricted to the syn conformational range while maintaining a full complement of normal hydrogen bonding sites. Detailed investigations of their conformational properties using nmr and molecular modeling techniques will be undertaken. The sulfone 1-3 is proposed as a potential bisubstrate inhibitor. Additional targets include the phosphonate 1-5, which is a derivative of a known uridine phosphorylase inhibitor, and a number of 2,2'-anhydrouridines (1-4) that feature anionic substituents at Cl'. These compounds might also function as bisubstrate or transition-state inhibitors. It is anticipated that the project will contribute to knowledge of enzyme-substrate/inhibitor interactions in the pyrimidine phosphorylase area. The capacity of the new compounds to inhibit uridine phosphorylase and other pyrimidine nucleoside phosphorylases will be determined by Dr. M. H. el Kouni at Brown University. The new compounds will also be examined in mammalian cell culture screens to check that they are not inherently cytotoxic. While animal studies are not proposed in this particular application, it should be noted that we do have ongoing arrangements in other projects for in vivo antitumor studies at Memorial Sloan Kettering Cancer Center. Therefore, a mechanism is already in place for follow-up studies in the event that the target compounds prove to be superior inhibitors of uridine phosphorylase.
| Schwartz, E L; Baptiste, N; Megati, S et al. (1995) 5-Ethoxy-2'-deoxyuridine, a novel substrate for thymidine phosphorylase, potentiates the antitumor activity of 5-fluorouracil when used in combination with interferon, an inducer of thymidine phosphorylase expression. Cancer Res 55:3543-50 |
