6-SUBSTITUTED AND 5,6-DISUBSTITUTED DERIVATIVES OF URIDINE - STEREOSELECTIVE SYNTHESIS, INTERACTION WITH URIDINE PHOSPHORYLASE, AND IN-VITRO ANTITUMOR-ACTIVITY
K. Felczak et al., 6-SUBSTITUTED AND 5,6-DISUBSTITUTED DERIVATIVES OF URIDINE - STEREOSELECTIVE SYNTHESIS, INTERACTION WITH URIDINE PHOSPHORYLASE, AND IN-VITRO ANTITUMOR-ACTIVITY, Journal of medicinal chemistry, 39(8), 1996, pp. 1720-1728
Stereoselective procedures are described for the synthesis of 6-alkylu
ridines by Lewis acid-catalyzed condensation of(a) trimethylsilylated
6-alkyl-4-alkylthiouracils with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-
ribofuranose (ABR) and (b) trimethylsilylated 6-alkyl-3-benzyluracils
with ABR. The 4-methylthio group was subsequently removed with the use
of 1 N trifluoroacetic acid and the 3-benzyl group by a new modified
procedure with the use of the complex BBr3-THF. Furthermore, 6-(hydrox
ymethyl)uridine (39) and 5-fluoro-6-(hydroxymethyl)uridine (40) were o
btained by sequential oxidation with SeO2 and reduction with tetrabuty
lammonium borohydride of the 6-methyl group of 6-methyluridine (5) and
5-fluoro-6-methyluridine (35), and their corresponding 6-fluoromethyl
congeners 41 and 42 were obtained by DAST treatment of 39 and 40, res
pectively. For all the foregoing nucleosides in the fixed syn conforma
tion about the glycosyl bond, H-1 NMR spectroscopy further demonstrate
d that the pentose rings exist predominantly in the conformation N (3'
-endo). Most of the nucleosides were weak substrates of Escherichia co
li pyrimidine nucleoside phosphorylase. Enhanced susceptibility to pho
sphorolysis was exhibited by two of them, 39 and 41, with 6-CH2OH and
6-CH2F substituents capable of formation of an additional hydrogen bon
d with the enzyme. The 5-fluoro-6-substituted uridines were the poores
t substrates. Cytotoxicities of the nucleosides were examined vs the h
uman tumor cell lines MOLT-3, U-937, K-562, and IM-9, as well as PHA-s
timulated human lymphocytes. Two of the analogues, 5-fluoro-6-(fluorom
ethyl)uridine (42) and 5-fluoro-6-(hydroxymethyl)uridine (40), exhibit
ed cytotoxicities comparable to that of 5-fluorouracil.