SYNTHESIS OF 2'-DEOXY-5-(ISOTHIAZOL-5-YL)URIDINE AND ITS INTERACTION WITH THE HSV-1 THYMIDINE KINASE

2'-Deoxy-5-(isothiazol-5-yl)uridine (12) was synthesized starting from 2'-deoxy-5-iodouridine using a Pd-catalysed cross-coupling reaction w ith propiolaldehyde diethyl acetal followed by deprotection and ring c losure using thiosulfate. 2'-Deoxyuridine 12 has a particular place am ong the 5-heteroaryl-substituted 2'-deoxyuridines in that it has a hig h affinity for herpes simplex virus type 1(HSV-1)-encoded thymidine ki nase (TK) without antiviral activity. Biochemical studies revealed tha t 12 is a substrate for viral TK. We further investigated the interact ion of 12 with the HSV-1 thymidine kinase. The conformation of 12 in s olution was established by NMR spectroscopy. The most stable conformer 12A has the S-atom of the isothiazole ring placed in the neighbourhoo d of the C(4)=O group of the pyrimidine moiety. The compound was docke d in its most stable conformation in the active site of HSV-1 TK and s ubjected to energy minimization. This demonstrated that the isothiazol e moiety binds in a cavity lined by the side chains of Tyr-132, Arg-16 3, Ala-167, and Ala-168 and that the C(3) atom of the isothiazole moie ty is located in close proximity of the phenolic O-atom of Tyr-132 and the aliphatic part of the Arg-163 side chain.