Syntheses of Novel Modified Acyclic Purine and Pyrimidine Nucleosides as Potential Substrates of Herpes Simplex Type-1 Thymidine Kinase for Monitoring Gene Expression

Suicide gene therapy with the herpes simplex virus type-1 thymidine kinase gene (HSV-1 tk) is considered to be a promising approach to the treatment of cancer. Making use of the lower specificity of the viral enzyme compared to human thymidine kinase, the therapy involves the administration of antiviral agents (e.g. ganciclovir) as prodrugs to induce enzymatic cell death in those cells that express the transferred gene. ¹⁸F labeled derivatives have been described for monitoring location, duration and magnitude of the viral kinase enzyme activity by positron emission tomography (PET). Since an optimal radiotracer has not been developed, novel substances were synthesized for monitoring gene expression. A group of 13 nucleoside analogues were synthesized, among them N¹-methyl-9-[(1,3-dihydroxy-2-propoxy)methyl]guanine 5 and N¹-methyl-9-[(4-hydroxy)-3-hydroxy-methylbutyl]guanine 7 as methyl analogues of ganciclovir and penciclovir and their related fluoro compounds (6, 8). Further novel derivatives include N⁶-methyl-9-[(1,3-dihydroxy-2-propoxy)methyl]-, N⁶-methyl-9-[(4-hydroxy)-3-hydroxymethylbutyl]adenine (9, 10) as well as the uracil derivatives 5-hydroxy-1-[(1,3-dihydroxy-2-propoxy)methyl]uracil 11, 6-methyl-1-[(1,3-dihydroxy-2-propoxy)-methyl]uracil 12 and its 3-fluoro-derivative 13.