Preparation, antibacterial effects and enzymatic degradation of 5-fluorouracil nucleosides

Abstract

Reaction of perbenzoylated aldopentafuranosyl derivatives of uracil with fluorine in acetic acid afforded perbenzoylated 5-fluorouracil nucleosides. Their methanolysis gave the following free nucleosides of 5-fluorouracil: β-D-ribofuranoside (Id), 2-deoxy-β-D-ribofuranoside (IId), their enantiomers VIII and IX, α-D-ribofuranoside (XIII), 2-deoxy-α-D-ribofuranoside (XV), β-D-arabinofuranoside (IV) and its L-enantiomer X, β-D-xylofuranoside (V) and its α-D-anomer XI, α-L-lyxofuranoside (VI) and 2-deoxy-α-L-lyxofuranoside (VII) and the enantiomers of the latter two compounds, XII and XIV, respectively. Analogously were obtained 5-deoxy-β-D-ribofuranoside (III), β-D-ribopyranoside (XVI) and 1-(S)-(2,3-dihydroxypropyl)-5-fluorouracil (XVIIc). 1-Allyl-5-fluorouracil (XVIII) was prepared by reaction of allyl bromide with 2,4-bis(trimethylsilyloxy)-5-fluoropyrimidine. The cell-free extract from Escherichia coli cleaves all the 5-fluorouracil nucleosides in which the nucleoside carbon atom has the R-configuration and the 3'-hydroxyl of the sugar moiety is in trans-relation to the base. Compounds which have not these structural features are resistant. Besides nucleosides which on enzymatic cleavage afford 5-fluorouracil, also the non-cleavable 1-(2-deoxy-β-L-ribofuranosyl)-5-fluorouracil (IX), 1-(2-deoxy-α-D-ribofuranosyl)-5-fluorouracil (XV) and 1-(2-deoxy-α-D-lyxofuranosyl)-5-fluorouracil (XIV) exhibit an antibacterial effect towards E. coli (ID50 1.0-2.5 . 10-5 M). This effect can be reversed by 2'-deoxyuridine but not by thymidine.

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

“…13,15 Perbenzoate 2 0 -deoxyuridine 87 was fluorinated with fluorine in acetic acid (60-90% yield). The benzoyl esters were removed from compound 88 by methanolysis affording floxuridine 61 (60-90% yield) 89 (Scheme 47).…”

Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry

“…In particular, 5′-deoxyrybose derivatives 56 , 57 , and 58 were used for that purpose (Scheme 11 ) [ 67 , 68 ]. Finally, direct fl uorination of 5′-deoxyuridine derivatives with F 2 /N 2 [ 69 ] or AcOF [ 70 ] was also described.…”

Application of elemental fluorine in organic synthesis

“…Susceptibility of ethers to oxidation by fluorine (entry 27) resulted in decreased hydrogen substitution as well as carbonyl-containing byproducts. 69 The substitution of tertiary hydrogens with fluorine has been extended to fluorination of various steroids (entries [34][35][36][37]. Monofluorination has been accomplished at the C-5 (/?…”

“…Similarly, l-methyl-5-fluoro-2-pyridone was prepared in 43% yield from l-methyl-2-pyridone.29 A nitrogen-diluted solution of fluorine reacted with pyrimidines for the synthesis of 5-fluorouracil, 6-fluorothymine, and many other important biochemical derivatives. [25][26][27][28][30][31][32][33][34][35][36][37][38][39][40][41] In the synthesis of 5-fluorouracil, Cech25 proposed that the reaction was initiated by syn addition of fluorine across the double bond, followed by solvent assisted elimination of F-. In acetic acid, an unstable acetoxy intermediate ( 5) is formed in this manner (eq 3).…”

“…In addition, many nucleosides of uracil derivatives have been fluorinated in the same manner with high yields. 25,28,31,32,34,40 Antipyrine (8), a lipophilic compound that has been shown to have a high uptake by the brain, can be selectively fluorinated in an aqueous medium27 or in glacial acetic acid to give the 4-fluoro derivative (9). 43 The preparation of its radiolabeled fluorinated analogue is expected to serve as a means for measurement of regional cerebral blood flow.…”