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

مجید چراغعلی

majid cheraghali leonard i. wiebe

rakesh kumar edward e. knaus

kevin w. morin kevin w. morin

edward e. knaus rakesh kumar

چکیده

(+)-trans-(5r,6r)-5-bromo-6-ethoxy-5-ethyl-5,6-dihydro-2&apos;-deoxyuridine [(5r,6r)-beedu], a po tential brain-targeted prodrug of 5-ethyl-2&apos;-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&apos; excretion into urine, after injection of [4 c] edu, was much faster than that after injection of [4- c]-(5r,6r)-beedu.

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عنوان ژورنال:
iranian biomedical journal

جلد ۲، شماره ۳، صفحات ۱۰۵-۱۱۳

کلمات کلیدی
[ 5 , ' e t h y l ' , 2 , ' d e o x y u r i d i n e ' , ' d i h y d r o p r o d r u g s ' , ' h e r p e s s i m p l e x v i r u s ' , ' b r a i n ' , ' t a r g e t e d ' ]

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