Syntheses of novel modified acyclic purine and pyrimidine nucleosides as potential substrates of herpes simplex virus type-1 thymidine kinase for monitoring gene expression
| Autor: | Bernd Johannsen, Michaela Grote, Bernhard Noll, Werner Kraus, Steffi Noll |
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| Rok vydání: | 2004 |
| Předmět: | |
| Zdroj: | Canadian Journal of Chemistry. 82:513-523 |
| ISSN: | 1480-3291 0008-4042 |
| DOI: | 10.1139/v04-005 |
| Popis: | 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-labelled 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-hydroxymethylbutyl]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).Key words: fluorinated nucleoside analogues, gene therapy, PET, thymidine kinase. |
| Databáze: | OpenAIRE |
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