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Novel Pyrimidine Nucleoside Analogs Comprising a Dihydroxyisoalkyl or Dihydroxyisoalkenyl Unit as Ligands for Gene Expression Monitoring

A large number of thymidine analogs and acyclic guanosine derivatives show antiviral activities against herpes simplex virus type 1 (HSV-1) and 2 (HSV-2). The antiviral activity of these compounds is due to their selective and efficient in vivo activation through monophosphorylation by the viral enzyme. The monophosphates are converted to diphosphates, and then to the corresponding triphosphates by cellular enzymes. The triphosphates prevent viral replication by inhibition of the viral DNA polymerase. HSV-1 TK in combination with a nucleoside analog as fraudulent substrate can be used as a suicide enzyme in the gene therapy of cancer. Furthermore, these compounds labeled with positron-emitting radioisotopes can be used as in situ reporter probes to allow noninvasive imaging of HSV-1 TK gene expression using positron emission tomography (PET). However, most of the PET reporter probes have several shortcomings, such as unfavorable cytotoxicity and pharmacokinetics. In the effort of further exploring the pyrimidine scaffold as putative starting point for development of novel PET tracers we have identified a new series of C-6 alkylated pyrimidines containing dihydroxyisobutyl and dihydroxyisobutenyl side chain at C-6 as HSV1-TK substrates. We also selected 5-(2-hydroxyethyl)pyrimidine with dihydroxyisopentyl at N-1 as a target compound. Newly prepared compounds exhibited no toxicity and showed better binding affinities in vitro for herpes simplex virus type 1 thymidine kinase (HSV1-TK) than prodrugs acyclovir and ganciclovir. The crystal structures of C-6 substituted pyrimidines in complex with HSV1-TK have been solved (Figure). The syntheses, biochemical and biological evaluations of unlabelled non-natural nucleoside analogues in vitro will be presented.

dihydroxyalkyl and dihydroxyalkenyl substituted nucleoside analogs; positron emission tomography; phosphorylation; herpes simplex type 1; gene expression monitoring

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