SYNTHESIS AND ANTIVIRAL AND CYTOTOXIC ACTIVITY OF IODOHYDRIN AND IODOMETHOXY DERIVATIVES OF 5-VINYL-2'-DEOXYURIDINES, 2'-FLUORO-2'-DEOXYURIDINE, AND URIDINE

A series of new 5-(1-hydroxy-2-iodoethyl)-2'-deoxyuridine and uridine compounds (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-vinyluridine (10c), and (E)-5-(2-iodovinyl)-2'-deoxyuridine (4b). Treatment of the iodohydrins 11a-c with methanolic sulfuric acid afforded the corresponding 5-(l-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-(l-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-(l-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(OMe)CH2I (12a) >CH(OH)CH2I (11a) ? 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-(l-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 Ki= 0.035-0.22 mM range relative to deoxyuridine,Ki= 0.125) for the murine NBMPR-sensitive erthyrocyte nucleoside transport system, suggesting that these iodohydrins are good permeants of cell membranes. © 1990, American Chemical Society. All rights reserved.