|
Title
|
|
|
|
Synthesis of 2'-deoxy-5-(isothiazol-5-yl)uridine and its interaction with the HSV-1 thymidine kinase
| |
|
Author
|
|
|
|
| |
|
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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Helvetica chimica acta. - Basel
| |
|
Publication
|
|
|
|
Basel
:
1996
| |
|
ISSN
|
|
|
|
0018-019X
| |
|
DOI
|
|
|
|
10.1002/HLCA.19960790519
| |
|
Volume/pages
|
|
|
|
79
:5
(1996)
, p. 1462-1474
| |
|
ISI
|
|
|
|
A1996VC76000018
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|