The objectives include the synthesis of novel antiviral and anticancer nucleoside analogs, to evaluate their spectra of activity both singly and in combination, to determine the site of inhibition and molecular basis for their inhibitory activity, and to prepare adequate amounts for evaluation in tumor bering animals and in a variety of virus infections in animals. The methodology includes development of novel approaches to synthesis of the nucleoside analogs, evaluation of their antiviral and anticancer activities in cell culture and then in animal systems using a variety of virus infections as well as a number of transplanted neoplasms. The long term objective is to develop clinically effective antiviral and anticancer agents. Our early efforts produced the clinically useful FDA approved antiviral agent Idoxuridine, and more recently 5'-amino nucleoside analogs with good potential as antivirals, and 3'-amino nucleosides and the corresponding 3'-nitrosourea analog with good anticancer activity have been synthesized. Because of the unique ability of the herpes simplex virus thymidine kinase, but not cellular thymidine kinase, to phosphorylate certain nucleoside analogs, such as 5-iodo-5'-amino-2',5'-dideoxyuridine (AIU, AIdUrd), it is possible to develop compounds that have little or no toxicity to uninfected cells, because these analogs are only activated (phosphorylated) in the virus infected cells. Equally as important is the finding that certain viral encoded enzymes, such as herpesvirus DNA polymerase, can be preferentially inhibited, thereby providing excellent antiviral activity at concentrations with little or no toxicity at the uninfected cell. Thus today we can take advantage of qualitative as well quantitative differences between the infected and uninfected cell in the design of antiviral agents. The basis for this very productive program is the combined efforts of several disciplines - organic chemistry biochemistry, virology and pharmacology. This combination has allowed maximal efficiency in the development of these therapeutic agents.
