Synthesis of 5-[1-hydroxy(or methoxy)-2-bromo(or chloro)ethyl]-2'-deoxyuridines and related halohydrin analogs with antiviral and cytotoxic activity

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Abstract
A series of new 5-(1-hydroxy-2-haloethyl)-2''-deoxyuridine (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2''-deoxyuridines (2, 5, 7). Treatment of 3a, b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2''-deoxyuridines (4a, b). The 5-(1-hydroxy-2-chloroethyl) (3b), 5-(1-methoxy-2-bromoethyl (4a), 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl) (6a), and 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl) (6b) derivatives exhibited in vitro antiviral activity (ID50 = 0.1-1 .mu.g/mL range) against herpes simplex virus type 1 (HSV-1). 5-(1-Hydroxy-2-bromo-2-(ethoxycarbonyl)-ethyl)-2''-deoxyuridine (6a) was the most active cytotoxic agent in the in vitro L1210 screen exhibiting an ED50 of 11 .mu.g/mL relative to melphalan (ED50 = 0.15 .mu.g/mL).