Synthesis and antiviral and cytotoxic activity of iodohydrin and iodomethoxy derivatives of 5-vinyl-2'-deoxyuridines, 2'-fluoro-2'-deoxyuridine, and uridine

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Abstract
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-(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-.beta.-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 .mu.g/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 .mu.g/mL range). The C-5 substituent in the 2''-deoxyuridine series was a detemrinant 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) .simeq. 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 .gtoreq. 11c; 12a > 12b > 12c). The most active cytotoxic agent (16), possessing a 5-(1-hydroxy-2,2-diiodoethyl) substituent (ED50 = 0.77 .mu.g/mL), exhibited an activity approaching that of melaphalan (ED50 = 0.15 .mu.g/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.