| Abstract
| - A new class of 5-(1-cyanamido-2-haloethyl)-2‘-deoxyuridines (4−6) and arabinouridines (7, 8)were synthesized by the regiospecific addition of halogenocyanamides (X-NHCN) to the 5-vinylsubstituent of the respective 5-vinyl-2‘-deoxyuridine (2) and 2‘-arabinouridine (3). Reaction of2 with sodium azide, ceric ammonium nitrate, and acetonitrile−methanol or water affordedthe 5-(1-hydroxy-2-azidoethyl)-(10) and 5-(1-methoxy-2-azidoethyl)-2‘-deoxyuridines (11). In vitroantiviral activities against HSV-1-TK+ (KOS and E-377), HSV-1-TK-, HSV-2, VZV, HCMV,and DHBV were determined. Of the newly synthesized compounds, 5-(1-cyanamido-2-iodoethyl)-2‘-deoxyuridine (6) exhibited the most potent anti-HSV-1 activity, which was equipotent toacyclovir and superior to 5-ethyl-2‘-deoxyuridine (EDU). In addition, it was significantlyinhibitory for thymidine kinase deficient strain of HSV-1 (EC50 = 2.3−15.3 μM). The 5-(1-cyanamido-2-haloethyl)-2‘-deoxyuridines (4−6) all were approximately equipotent againstHSV-2 and were ∼1.5- and 15-fold less inhibitory for HSV-2 than EDU and acyclovir,respectively. Compounds 4−6 were all inactive against HCMV but exhibited appreciableantiviral activity against VZV. Their anti-VZV activity was similar or higher to that of EDUand approximately 5−12-fold lower than that of acyclovir. The 5-(1-cyanamido-2-haloethyl)-(7,8) analogues of arabinouridine were moderately inhibitory for VZV and HSV-1 (strain KOS),whereas compounds 10 and 11 were inactive against herpes viruses. Compounds 5 and 6 alsodemonstrated modest anti-hepatitis B virus activity against DHBV (EC50 = 19.9−23.6 μM).Interestingly, the related 5-(1-azido-2-bromoethyl)-2‘-deoxyuridine (1n) analogue proved to bemarkedly inhibitory to DHBV replication (EC50 = 2.6−6.6 μM). All compounds investigatedexhibited low host cell toxicity to several stationary and proliferating host cell lines as well asmitogen-stimulated proliferating human T lymphocytes.
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