title: C-5 hydroxyethyl and hydroxypropyl acyclonucleosides as substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK): syntheses and biological evaluation.
abstract: The efficient syntheses of 5-(2-hydroxyethyl)- and 5-(3-hydroxypropyl)-substituted pyrimidine derivatives bearing 2,3-dihydroxypropyl, acyclovir-, ganciclovir- and penciclovir-like side chains are reported. A synthetic approach that included the alkylation of an N-anionic-5-substituted pyrimidine intermediate (method A) provided the target acyclonucleosides in significantly higher overall yields in comparison to those obtained by method B using sylilation reaction. The phosphorylation assays of novel compounds as potential substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK) showed that solely pyrimidine 5-substituted acyclonucleosides with a penciclovir-like side chain acted as a fraudulent substrates of HSV-1 TK. Moreover, the uracil derivative with penciclovir-like side chain with less bulky 2-hydroxyethyl substituent at C-5 proved to be a better substrate than the corresponding one with a 3-hydroxypropyl substituent. Therefore, this acyclonucleoside was selected as a lead compound for the development of a positron emission tomography HSV-1 TK activity imaging agent.
authors: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia.
authors: Andrijana
authors: A
authors: Meščić
authors: Svjetlana
authors: S
authors: Krištafor
authors: Ivana
authors: I
authors: Novaković
authors: Amar
authors: A
authors: Osmanović
authors: Ursina
authors: U
authors: Müller
authors: Davorka
authors: D
authors: Završnik
authors: Simon M
authors: SM
authors: Ametamey
authors: Leonardo
authors: L
authors: Scapozza
authors: Silvana
authors: S
authors: Raić-Malić
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents; D002460:Cell Line; D005347:Fibroblasts; D015774:Ganciclovir / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006147:Guanine; D006561:Herpes Simplex / Q000000981:diagnostic imaging / Q000201:enzymology; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011859:Radiography; D013937:Thymidine Kinase / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; C053539:penciclovir; D006147:Guanine; D013937:Thymidine Kinase; D015774:Ganciclovir; D000212:Acyclovir
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