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C-5 Hydroxyethyl and Hydroxypropyl Acyclonucleosides as Substrates for Thymidine Kinase of Herpes Simplex Virus Type 1 (HSV-1 TK): Syntheses and Biological Evaluation
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
Pharmaceutical Biochemistry, School of Pharmaceutical Sciences, University of Geneva, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Sarajevo, Zmaja od Bosne 8, BIH-71 000 Sarajevo, Bosnia and Herzegovina
Center for Radiopharmaceutical Sciences, ETH Zurich (Swiss Federal Institute of Technology), Wolfgang-Pauli Strasse 10, CH-8093 Zurich, Switzerland
* Author to whom correspondence should be addressed.
Received: 31 January 2013; in revised form: 16 April 2013 / Accepted: 25 April 2013 / Published: 2 May 2013
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.
Keywords: acyclic nucleoside analogues; 5-substituted pyrimidines; herpes simplex virus type 1 thymidine kinase (HSV-1 TK); positron emission tomography (PET)
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Meščić, A.; Krištafor, S.; Novaković, I.; Osmanović, A.; Müller, U.; Završnik, D.; Ametamey, S.M.; Scapozza, L.; Raić-Malić, S. C-5 Hydroxyethyl and Hydroxypropyl Acyclonucleosides as Substrates for Thymidine Kinase of Herpes Simplex Virus Type 1 (HSV-1 TK): Syntheses and Biological Evaluation. Molecules 2013, 18, 5104-5124.
Meščić A, Krištafor S, Novaković I, Osmanović A, Müller U, Završnik D, Ametamey SM, Scapozza L, Raić-Malić S. C-5 Hydroxyethyl and Hydroxypropyl Acyclonucleosides as Substrates for Thymidine Kinase of Herpes Simplex Virus Type 1 (HSV-1 TK): Syntheses and Biological Evaluation. Molecules. 2013; 18(5):5104-5124.
Meščić, Andrijana; Krištafor, Svjetlana; Novaković, Ivana; Osmanović, Amar; Müller, Ursina; Završnik, Davorka; Ametamey, Simon M.; Scapozza, Leonardo; Raić-Malić, Silvana. 2013. "C-5 Hydroxyethyl and Hydroxypropyl Acyclonucleosides as Substrates for Thymidine Kinase of Herpes Simplex Virus Type 1 (HSV-1 TK): Syntheses and Biological Evaluation." Molecules 18, no. 5: 5104-5124.