title: Synthesis, 18F-radiolabelling and biological evaluations of C-6 alkylated pyrimidine nucleoside analogues.
abstract: Synthesis of pyrimidine derivatives with a side-chain attached to the C-6 of pyrimidine ring (6-14) is reported. Target compounds 8 and 12 were subjected to in vitro phosphorylation tests, determination of their binding affinities to herpes simplex virus (HSV-1) thymidine kinase (TK) and catalytic turnover constants. Fluorinated pyrimidine derivative 12 (40 microM) exhibited better binding affinity for HSV-1 TK than acyclovir (ACV, 170 microM) and ganciclovir (GCV, 48 microM). Catalytic turnover constant (k(cat)) of 12 (0.08 s(-1)) was close to the k(cat) values of ACV (0.10 s(-1)) and GCV (0.10 s(-1)). Furthermore, compounds 8 and 12 showed no cytotoxic effects in HSV-1 TK-transduced and non-transduced cell lines. Besides, compounds 8 and 12 did not exhibit antiviral or cytostatic activities against several viruses and malignant tumor cell lines that were evaluated. The new fluorinated pyrimidine derivative 16 that is phosphorylated by HSV-1 TK could be developed as non-toxic PET-tracer molecule. Thus, 18F labelling of the precursor 14 was performed by nucleophilic substitution using [18F] tetrabutylammonium fluoride as the fluorinating reagent.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia. silvana.raic@fkit.hr
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
authors.forename: Anass
authors.initials: A
authors.lastname: Johayem
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: Sanja
authors.initials: S
authors.lastname: Batinac
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Gerd
authors.initials: G
authors.lastname: Folkers
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
mesh_terms: D000478:Alkylation; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D005462:Fluorine Radioisotopes; D015774:Ganciclovir / Q000378:metabolism / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors
chemical_list: D000998:Antiviral Agents; D005462:Fluorine Radioisotopes; D011741:Pyrimidine Nucleosides; D013937:Thymidine Kinase; D015774:Ganciclovir