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.

DOI: 10.3390/molecules18055104

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@article{Mei2013C5HA, 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.}, author={Andrijana Me{\vs}{\vc}i{\'c} and Svjetlana Kri{\vs}tafor and Ivana V. Novakovi{\'c} and Amar Osmanovi{\'c} and Ursina M{\"{u}ller and Davorka Zavr{\vs}nik and Simon M. Ametamey and Leonardo Scapozza and Silvana Rai{\'c}-Mali{\'c}}, journal={Molecules}, year={2013}, volume={18 5}, pages={5104-24} }