Activation by thymidine kinase and potent antiherpetic activity of 2′-nor-2′-deoxyguanosine (2′NDG)

In an investigation of the substrate specificity of herpes simplex type I (HSV-1) thymidine kinase, certain chemical analogs of acyclovir were prepared. One of these, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (2′-nor-2′-deoxyguanosine, 2′NDG), prepared in a five-step convergent synthesis from glycerol formal and guanine, was a more efficient substrate for thymidine kinase (HSV-1) and GMP kinase and was more rapidly converted to the corresponding triphosphate derivative in virus-infected cells than was the known antiherpetic agent, acyclovir. 2′NDG showed antiherpetic activity in cell culture (HSV-1 and HSV-2 in primary rabbit kidney cells) equivalent to acyclovir. In an in vivo comparison of 2′NDG with five other known antiherpetic agents including acyclovir for protection of mice against HSV-1 induced encephalitis, 2′NDG was at least 60-fold more effective. There was no effect on cell viability in culture and no depression of weight gain or other evidence of toxicity in mice which could be attributed to treatment with 2′NDG.