Fluorinated nucleotides

Hudarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine. Its cytotoxicity is not well understood. It is rapidly dephospho-rylated at the cell membrane level and then rephos-phorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. It inhibits DNA polymerase and DNA primase. It is also incorporated into DNA and RNA. Hudarabine is administered intravenously by infusion over 30-120 min. It is eliminated by renal excretion with a terminal half life 10 hours. Adverse effects include myelosuppres-sion, nausea, vomiting, chills and fever. The number of CD4 positive cells is reduced and the incidence of opportunistic infections is increased. 

Fludarabine is a purine antimetabolite. Fludarabine is a fluorinated nucleotide analog of the antiviral agent vidara-bine. Fludarabine s metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis. It is indicated in refactory or progressive chronic B-ceU lymphocytic leukemia. 

P. Reyes and C. Heidelberger, Fluorinated pyrimidines. XXVI. Mammalian thymidylate synthetase Its mechanism of action and inhibition by fluorinated nucleotides. Mol. Pharmacol. /, 14 (1965). 

Fluorinated dithioester 39 has also been involved in thioacylation reaction of enantiopure aminoalcohols leading to the corresponding hydroxylated thioamides. The later, treated either by SOCVpyridine, CH3SO2CI, or PhjP/DEAD, cyclise into thiazolines 42 without epimerisation and in excellent yields. An interesting application of this reaction is the synthesis of a new type of modified nucleotides such as 43 and 44 by a one pot reaction simply by mixing the dihydroxy substituted thioamide (obtained from 39 and the 2-amino-l,3-... 

The pyrimidine bases, their derivatives, nucleotides, and nucleosides have been extensively studied by NMR techniques including proton magnetic resonance (PMR), carbon-13, nitrogen-15, and fluorine-19 magnetic resonances as well as nitrogen-14 nuclear qxiadrupole resonance (14N NQR). 

P. Herdewijin, A. Van Aerschot, and L. Kerreinans, Synthesis of nucleosides fluorinated in the sugar moiety, Nucleosides Nucleotides 8 65 (1989). 

Salts of the tetrafluoroaluminate (TFA) anion have been known for many years. Yet aqueous routes to pure materials have not been established despite the substantial amount of literature available on the subject. The present review will discuss the various synthetic methods that have been employed and will demonstrate a revised method for preparing pure TFA salts. These materials are important because TFA is able to stimulate various guanosine nucleotide-binding proteins (G-proteins) and inhibit P-type ATPases by serving as a nonhydrolyzing phosphate mimic. Additionally, various TFA salts serve as precursors to aluminum trifluoride, which is used as a catalyst for chlorofluorocarbon isomerizations and fluorinations. 

The most widely known chemotherapeutic agent directed against TS is 5-fluorour-acil (5-FU). 5-FU was first used clinically almost 50 years ago, yet still remains a mainstay for the treatment of carcinoma of the breast and gastrointestinal tract. In cells, 5-FU is metabolized to 5-FdUMP, which forms a stable inhibitory ternary complex with the co-substrate N5N10-methylene-5,6,7,8-tetrahydrofolate (CH2H4-folate) and TS. In this complex, a covalent bond links the thiol of cysteine 195 of human TS to C6 of deoxyuracil monophosphate (dUMP) and the methylene carbon of the co-substrate is joined to C5 of the nucleotide [55]. The fluorine at C5, unlike the proton, cannot... 

Siddiqui, M. A., Driscoll, J. S., Abushanab, E., et al. (2000) The P-fluorine effect in the non-metal hydride radical deoxygenation of fluorine-containing nucleoside xanthates. Nucleosides, Nucleotides, Nucleic Acids, 19, 1-12. 

Hollenstein, M., Gautschi, D. and Leumann, C. J. (2003) Fluorinated peptide nucleic acids. Nucleosides Nucleotides Nucleic Acids, 22, 1191-1194. 

Fluorouracil (5-FU) is a fluorinated analog of the naturally occurring pyrimidine uracil, originally synthesized in the late 1950s (Table 124—11). It is a prodrug and must be metabolized to the nucleotide form, fluorodeoxyuridine monophosphate (FdUMP), to be active. In the presence of folates, FdUMP binds tightly to and interferes with... 

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