Synthesis and Antiviral and Cytotoxic Activity of Iodohydrin and Iodomethoxy Derivatives of 5-Vinyl-2'-deoxyuridines, 2'-Fluoro-2'-deoxyuridine, and Uridine

Article abstract of DOI:10.1021/jm00164a039

A series of new 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine and uridine cpmpounds (11, 16) was synthesized by the regiospecific addition of HOI to the vinyl substituent of 5-vinyl-2'-deoxyuridine (10a), 5-vinyl-2'-fluoro-2'-deoxyuridine (10b), 5-vinyl-uridine (10c), and (E)-5-(2-iodovinyl)-2'-deoxyuridine (4b).Treatment of the iodohydrins 11a-c with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-iodoethyl) derivatives (12a-c).In contrast, reaction of 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine (11a) with sodium carbonate in methanol afforded a mixture of 5-(1-hydroxy-2-methoxyethyl)-2'-deoxyuridine (13) and 2,3-dihydro-3-hydroxy-5-(2'-deoxy-β-D-ribofuranosyl)furano<2,3-d>pyrimidin-6(5H)-one (14).The most active compound, 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (12a, ID₅₀ = 0.1 μg/mL) which exhibited antiviral activity (HSV-1) 100-fold higher than that of the 5-(1-hydroxy-2-iodoethyl) analogue (11a), was less active than IVDU or acyclovir (ID₅₀ = 0.01 - 0.1 μg/mL range).The C-5 substituent in the 2'-deoxyuridine series was a determinant of cytotoxic activity, as determined in the in vitro L1210 screen, where the relative activity order was CH(OH)CHI2 (16) > CH(OH)CH2I (11a) ca.CH(OH)CH2OMe (13).The 2'-substituent was also a determinant of cytotoxic activity in the 5-(1-hydroxy-2-iodoethyl) (11a-c) and 5-(1-methoxy-2-iodoethyl) series of compounds, where the relative activity profile was 2'-deoxyuridine > 2'-fluoro-2'-deoxyuridine > uridine (11a > 11b <*> 11c; 12a > 12b > 12c).The most active cytotoxic agent (16), possessing a 5-(1-hydroxy-2,2-diiodoethyl) substituent (ED₅₀ = 0.77 μg/mL), exhibited an activity approaching that of melphalan (ED₅₀ = 0.15 μg/mL).All compounds tested, except for 13 and 14, exhibited high affinity (K_i = 0.035 - 0.22 mM range relative to deoxyuridine, K_i = 0.125) for the murine NBMPR-sensitive erthyrocyte nucleoside transport system, suggesting that these iodohydrins are good permeants of cell membranes.