evaluation of (5r,6r)-5-bromo-6-ethoxy-5-ethyl-5,6-dihydro-2'- deoxyuridine as a brain-targeted prodrug of 5-ethyl-2'- deoxyuridine
نویسندگان
چکیده
(+)-trans-(5r,6r)-5-bromo-6-ethoxy-5-ethyl-5,6-dihydro-2'-deoxyuridine [(5r,6r)-beedu], a po tential brain-targeted prodrug of 5-ethyl-2'-deoxyuridine (edu), was synthesized by the regiospecific addition of broet to the 5,6-olefinic bond of edu. (5r,6r)-beedu is more lipophilic (log p = 0.04) than edu (log p = -1.09). in vitro incubation of (5r,6r)-beedu with rat whole blood and brain ho mogenate resulted in a 53% and 16% conversion, respectively, to edu. in contrast, (5r,6r)-beedu was not converted to edu upon incubation with glutathione (gsh) at 37°c for 36 hours. after i.v. injection into rats, (5r,6r)-beedu was rapidly converted to edu, which was then further metabo lized like edu. however, (5r,6r)-beedu provided a substantially higher ryncentration of edu in blood, relative to that when edu was injected. a biodistribution study of [4- c]-(5r,6r)-beedu in balb/c mice showed that (5r,6r)-beedu provided significantly higher (p < 0.05) radirctivityievels in brain samples at 8, 18 and 30 min post injection than observfid after injection of [4- c]-edu. the higher repioactivity levels in liver samples after injection of [4- c]-(5r,6r)-beedu, relative to those after [4- c]-edu, indicates that the 5,6-dihydro derivative undergoes a higher hepatic extraition than edu. clearance of radioactivity from blood qv' excretion into urine, after injection of [4 c] edu, was much faster than that after injection of [4- c]-(5r,6r)-beedu.
منابع مشابه
Evaluation of (5R,6R)-5-Bromo-6-Ethoxy-5-Ethyl-5,6-Dihydro-2\'- Deoxyuridine as a Brain-Targeted Prodrug of 5-Ethyl-2\'- Deoxyuridine
(+)-Trans-(5R,6R)-5-bromo-6-ethoxy-5-ethyl-5,6-dihydro-2'-deoxyuridine [(5R,6R)-BEEDU], a potential brain-targeted prodrug of 5-ethyl-2'-deoxyuridine (EDU), was synthesized by the regiospecific addition of BrOEt to the 5,6-olefinic bond of EDU. (5R,6R)-BEEDU is more lipophilic (log P = 0.04) than EDU (log P = -1.09). In vitro incubation of (5R,6R)-BEEDU with rat whole blood and brain homogena...
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عنوان ژورنال:
iranian biomedical journalجلد ۲، شماره ۳، صفحات ۱۰۵-۱۱۳
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