Potential radiosensitizing antiviral and anticancer pyrimidine nucleosides. Final report, June 1, 1974--May 31, 1978

The synthesis of a variety of novel nucleosides as potential antiviral, antineoplastic, and radiation sensitizing agents was investigated. The most significant accomplishment of this period was the development of 5-Iodo-5'-amino-2',5'-dideoxyuridine (AIU, AIdUrd) which is the first compound to require unequivocally, for antiviral activity, a unique activation by an enzyme (thymidine kinase) encoded by the Herpes virus genome. This unusual requirement for activation prevents toxicity to uninfected cells or tissues. The major conceptual contribution is that a non-toxic drug for established viral infections can indeed be developed. Although AIU is not a substrate for E. coli thymidine- or thymidylate kinase, it does bind to these enzymes and has a K/sub i/ of 240 ..mu..M and 59 ..mu..M respectively. Both enzymes are sensitized to uv radiations, and the concentrations required for 50 percent enhancement is roughly equivalent to their respective K/sub i/. Various other halogenated nucleoside analogs were prepared and evaluated for radiation sensitization potential. Mammalian enzymes appear to be less sensitive to uv radiations than bacterial enzymes. In an attempt to overcome this problem 5'-azido nucleoside analogs were prepared, but these were not effective