6-Azapyrimidine-2'-deoxy-4'-thionucleosides: potent antiviral agents in TK+ and TK- HSV and VZV viral strains

Maslen, Hannah L, Hughes, David, Hursthouse, Mike, De Clercq, Erik, Balzarini, Jan and Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 2004. 6-Azapyrimidine-2'-deoxy-4'-thionucleosides: potent antiviral agents in TK+ and TK- HSV and VZV viral strains. Journal of Medicinal Chemistry 47 (22) , pp. 5482-5491. 10.1021/jm049806q

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Abstract

The synthesis of a series of novel 1-(2-deoxy-4-thio-?-d-erythro-pentofuranosyl)-(6-azapyrimidine) nucleosides is described. X-ray crystallographic data of the thymidine derivative allowed conformational analysis, which indicated a twist (3T2) sugar conformation. Hydrogen-bonded assemblies for the crystal structure were determined using PLATON software to allow further interpretation of the crystal packing and base interactions. The 6-azapyrimidine nucleosides described were evaluated against a range of viral strains. The thymidine analogue showed pronounced activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and vaccinia virus. This compound lost only 5- to 10-fold of its antiviral activity against thymidine kinase (TK)-deficient HSV-1 and VZV strains. These observations suggest that the compounds may not entirely depend on viral TK-catalyzed phosphorylation for antiviral activity and/or use an alternative metabolic activation pathway, and/or display a unique mechanism of antiviral action by the unmetabolized nucleoside analogue.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
ISSN:	00222623
Last Modified:	17 Oct 2022 08:45
URI:	https://orca.cardiff.ac.uk/id/eprint/947

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