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Molecules 2013, 18(5), 5104-5124; doi:10.3390/molecules18055104
Article

C-5 Hydroxyethyl and Hydroxypropyl Acyclonucleosides as Substrates for Thymidine Kinase of Herpes Simplex Virus Type 1 (HSV-1 TK): Syntheses and Biological Evaluation

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Received: 31 January 2013; in revised form: 16 April 2013 / Accepted: 25 April 2013 / Published: 2 May 2013
(This article belongs to the Section Medicinal Chemistry)
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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) acyclic nucleoside analogues; 5-substituted pyrimidines; herpes simplex virus type 1 thymidine kinase (HSV-1 TK); positron emission tomography (PET)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

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.

Chicago/Turabian Style

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.



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