Title
Synthesis of 2'-deoxy-5-(isothiazol-5-yl)uridine and its interaction with the HSV-1 thymidine kinase
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Basel ,
Subject
Chemistry
Source (journal)
Helvetica chimica acta. - Basel
Volume/pages
79(1996) :5 , p. 1462-1474
ISSN
0018-019X
ISI
A1996VC76000018
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
2'-Deoxy-5-(isothiazol-5-yl)uridine (12) was synthesized starting from 2'-deoxy-5-iodouridine using a Pd-catalysed cross-coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2'-Deoxyuridine 12 has a particular place among the 5-heteroaryl-substituted 2'-deoxyuridines in that it has a high affinity for herpes simplex virus type 1(HSV-1)-encoded thymidine kinase (TK) without antiviral activity. Biochemical studies revealed that 12 is a substrate for viral TK. We further investigated the interaction of 12 with the HSV-1 thymidine kinase. The conformation of 12 in solution was established by NMR spectroscopy. The most stable conformer 12A has the S-atom of the isothiazole ring placed in the neighbourhood of the C(4)=O group of the pyrimidine moiety. The compound was docked in its most stable conformation in the active site of HSV-1 TK and subjected to energy minimization. This demonstrated that the isothiazole moiety binds in a cavity lined by the side chains of Tyr-132, Arg-163, Ala-167, and Ala-168 and that the C(3) atom of the isothiazole moiety is located in close proximity of the phenolic O-atom of Tyr-132 and the aliphatic part of the Arg-163 side chain.
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