Fluoro nucleoside

In the field of nucleosides, an interesting example of a cleavage of a nonfluor-inated six-membered cyclic ether containing oxygen and nitrogen atoms to give a fluoro nucleoside has been reported [5] (equation 5)... 

Many fluorosugars have been prepared with the aid of Bu4NF. In most reactions the nucleophilic fluorine substitutes the excellent leaving triflate, usually with inversion of configuration. Thus, 2-deoxy-2-fluoroglucose, 6102, and fluoroarabinose were made (equation 54). These serve as precursors for fluoro-antibiotics103 and fluoro-nucleosides with... 

Aptamers incorporating 2 -fluoro-nucleoside from L-arabinose have also been selected that bind to neuropeptides. ... 

Different synthetic routes have been described for synthesis of 2 -modified nucleosides [152]. 2 -Fluoro nucleosides are usually prepared starting from arabinofuranosylnucleosides. 2,2 -Anhydroarabinofuranosyluracil 61 has been reported to yield 2 -deoxy-2 fluorouridine upon treatment with hydrogen fluoride. 2 -Amino-2-deoxyuridine may be easily prepared by similar rearrangements in large scale synthesis [153]. Synthesis of 2 -deoxy-2 -fluoropurine... 

Moreover, where studied (3,i), the 2 -fluoro nucleosides were resistant to catabolic cleavage by nucleoside phosphorylases, presumably a result of the increased metabolic stability of the N-glycosyl linkage imposed by this electronegative 2 -substituent. Of the several 2 -fluoro—5-substituted—arabinosyl pyrimidine nucleosides synthesized (1.), l-(2 -deozy-2 -fluoro-3-D-arabinofuranosy 1 )-5-iodo-cytosine [FIAC] has demonstrated clinical efficacy against Herpesvirus infections in Phase 1 (5,) and against Varicella zoster virus in Phase 2 ( ) clinical trials in immunocompromised cancer patients. 

A phosphoramidite and a methylphosphonamidite of 2 -D-methylisocytidine have been prepared, and used for incorporation into oligonucleotide analogues. Di(2 -deoxy-2 -fluoro)nucleoside phosphates and phosphorothioates have been prepared, and their stability to snake venom phosphodiesterase was investigated. ... 

Cytidine has been converted into l-(5-amino-5-deoxy-j8-D-arabinofuranosyl) cytosine by a sequence of reactions involving A-benzoylation, sulphonation, acetylation, displacement with azide ion, e/c., and l-(3-amino-3-deoxy-jS-D-arabinofuranosyl)-6-azauracil was derived from 2, 3 -di-0-methanesulphonyl-5 -O-trityl-6-azauridine via 2,2 - and 2, 3 -anhydro-nucleosides. Other syntheses have been accomplished by the condensation of an appropriately derivatized amino-sugar with either a pyrimidine or purine derivative for example, the Hilbert route was used to prepare l-(2-amino-2-deoxy-a-D-arabino- and -jS-o-xylo-furanosyl)cytosine. > The reactivity of l,3,4,6-tetra-0-acetyl-2-acyl-amido-2-deoxy-j3-D-glucopyranoses in condensation reactions with 2,6-dichloro-purine, theophylline, and 6-benzylaminopurine was shown to be in the order benzamido > acetamido > phthalimido. 9-(3-Acetamido-2,5-di-0-acetyl-3-deoxy-j8-D-ribofuranosyl)-2,6-dichloropurine has been synthesized and converted into the corresponding 2,6-diamino- and 6-amino-2-chloro(fluoro)-nucleosides. ... 

In contrast to the readily conversion of di-O-isopropylidene-D-allose (76) into the 3-/3-fluoro derivative 77 with DAST, the same treatment of 32 did not afford the corresponding 3 -/8-fluoro nucleoside 84 (Scheme 14) but only decomposition products. Molecular modeling studies revealed that the conformation of 32 is the same as that of 3, 5 -di-O-trityl isomer 31, Le., CT-endo. In this conformation H 2 and HO at C 3 are in the trans quasi diaxial disposition, favoring elimination. This conformational feature may account for decomposition of 32 upon treatment with DAST, although the participation of N of the adenine aglycon in reaction involving... 

Purine, 2,6-dithioxo-1,2,3,6-tetrahydro-dethiation, 5, 558 Purine, 8-ethoxy-synthesis, 5, 577, 596 Purine, 6-ethoxycarbonylmethyl-nucleoside synthesis, 5, 561 Purine, 8-ethoxy-7-methyl-synthesis, 5, 577 Purine, 9-ethyl-synthesis, 5, 593 Purine, 6-fonnyl-reactions, 5, 547 synthesis, 5, 593 Purine, 8-fonnyl-reactions, 5, 547 Purine, 2-fluoro-synthesis, 5, 597 Purine, 6-fluoro-alkylation, 5, 529 synthesis, 5, 563, 573 Purine, 6-fluoro-9-methyl-reactions, with ammonia, 5, 562 Purine, 6-furfurylamino- — see Kinetin Purine, 9-glycofuranosyl-synthesis, 5, 572 Purine, 2-glycosyl-synthesis, 5, 587 Purine, 8-glycosyl-synthesis, 5, 585 Purine, 9-glycosyl-synthesis, 5, 572 Purine, 8-halo-synthesis, 5, 598 Purine, 2-hydrazino-synthesis, 5, 593 Purine, 8-o -hydroxyethyl-synthesis, 5, 574... 

Hurwitz SJ, Schinazi RF (2002) Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. Antiviral Res 56 115-127 Hurwitz SJ, Tennant BC, Korba BE, Gerin JL, Schinazi RF (1998) Pharmacodynamics of (—)-beta-2, 3 -dideoxy-3 -thiacytidine in chronically virus-infected woodchucks compared to its pharmacodynamics in humans, Antimicrob Agents Chemother 42 2804-2809 Hurwitz SJ, Otto MJ, Schinazi RF (2005) Comparative pharmacokinetics of Racivir, (+/-)-beta-2, 3 -dideoxy-5-fluoro-3 -thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans, Antivir Chem Chemother 16 117-127... 

Nucleoside inhibitors of hepatitis C virus RNA polymerase improved potency and liver targeting with 7-deaza-7-fluoro-2 -C-methyladenosine. In Late breaker presentations. 20th international conference on antiviral research, Palm Springs, CA, USA, April 29-May 3, 2007, LB-01... 

Wang J, Jin Y, Rapp KL, Schinazi RF, Chu CK (2007) D- and L-2, 3 -didehydro-2, 3 -dideoxy-3 -fluoro-carbocyclic nucleosides synthesis, anti-HIV activity and mechanism of resistance. J Med Chem 50 1828-1839... 

Preparation of 2-fluorofuranoses is also important in relation to the synthesis of biologically active 2 -fluoro derivatives of nucleosides (see Section 111,4). Su and coworkers prepared the 2-triflates 236 and 239 through acid-catalyzed methanolysis of 3,5-di-O-benzyl-1,2-(9-isopropylidene-a-D-ribofuranose [to give 235 (major) and 238] and subsequent triflylation. On treatment with fluoride ion, the anomer 236 afforded exclusively the furan derivative 237, whereas the a anomer 239 gave the 2-fluoro compound 240... 

Because synthesis of l-(2-deoxy-2-fluoro-)S-D-arabinofuranosyl)cytosine (744, FAC), an elementary arabino type of nucleoside having a growth-inhibitory effect against L 1210 leukemia in mice, through direct introduction of a fluorine atom in the 2 - up (arabino) position was difficult, compound 744 was prepared by condensation of trimethylsilylated A -acetylcytosine with 3-0-acetyl-5-(7-benzoyl-2-deoxy-2-fluoro-D-arabin-ofuranosyl bromide (742), which had been prepared by periodate oxidation of 6-0-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (741). Similar condensa-... 

Many 5-alkyl-, 5-alkenyl-, and 5-alkynyl-l-(2-deoxy-2-fluoro- 5-D-arabin-ofuranosyl)pyrimidines (750 - 752 and 765 - 767) were prepared - " by condensation of 742 (or the equivalent, such as 743) with C-5-substituted pyrimidine derivatives, or by attachment of a C-fragment to C-5 of the existing nucleosides through their 5-iodo or 5-chloromercuri derivatives, or by further conversion of the attached C-5 substituent into another one. ... 

Different kinds of nucleosides (778) were prepared by condensation of compound 400 (see Section 11,3) with trimethylsilylated uracils under Lewis acid catalysis, and removal of one fluorine atom at C-2 of the sugars. Uridine 5 -(2-acetamido-2,4-dideoxy-4-fluoro-a-D-galactopyranosyl di-... 

The 2 -chloro and 2 -bromo congeners of either 748 (FIAC) or 758 (FMAU) are more cytotoxic than FIAC and FMAU, suggesting that these chloro and bromo nucleosides, in contrast to the 2 -fluoro compounds, are comparatively better substrates for deoxycytidine kinase of human lymphocytes than the substrates for viral-specific thymidine kinase. The disposition of the 2 -fluoro group may also be important from the biological viewpoint. It should be noted that the structural difference between RNA and DNA is at the 2 -position. The ribo type of analog (738) of FIAC is 10 times less effective in suppression of HSV replication than is FIAC. Thus Fox, and Watanabe and coworkers concluded that the 2 - up fluorine disposition and the species of the substituent at C-5 are the two important factors influencing antiviral activity. Nevertheless, the mechanism of action of 2 -deoxy-2 -fluorocytidine (737) on certain herpes viruses, including HSV-1... 

Nucleosides containing deoxyfluoroglycopyranosyl residues were also prepared. 1-(6-Deoxy-6-fluoro-/ -D-gluco- and -galacto-pyranosyl)thymine (858 and 860) were obtained from l-/ -D-gluco- and -galacto-pyranosyl-thymine by the usual displacement reaction, or by the condensation method. 

Removal of the 2 -sulfonyloxy group of 859 in a basic medium, followed by reaction with metal halides (LiBr and Nal) or hydrogen halides (HCl-1,4-dioxane, HBr-acetone, or0.1% HFin l,4-dioxane-AlF3)gave, byway of the 2,2 -anhydro intermediate 861, the 2 -halo derivatives 862-865. The 2 -deoxy analog 866 and l-(6-deoxy-6-fluoro- ff-D-mannopyranosyl)thy-mine were also prepared from 864 (R = H) and 861 (R = H), respectively. l-(4-Deoxy-4-fluoro-y -D-glucopyranosyl)thymine was obtained by the condensation method. A different kind of nucleoside, 5-(5-deoxy-5-fluoro-2,3-0-isopropylidene-a-D-ribofuranosyl)-l,3-dimethyluracil has also been prepared. ... 

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