Ribonucleosides

CH2(OMe)2, CH2 = CHCH2SiMe3, MeaSiOTf, P2O5, 93-99% yield." This method was used to protect the 2 -OH of ribonucleosides and deoxyribo-nucleosides as well as the hydroxyl groups of several other carbohydrates bearing functionality such as esters, amides, and acetonides. 

The CPTr group was developed for the protection of the 5 -OH of ribonucleosides. It is introduced with CPTrBr/AgN03/DMF (15 min) in 80-96% yield and can be removed by ammonia followed by 0.01 M HCl or 80% AcOH. It can also be removed with hydrazine and acetic acid. ... 

The pixyl ether is prepared from the xanthenyl chloride in 68-87% yield. This group has been used extensively in the protection of the 5 -OH of nucleosides it is readily cleaved by acidic hydrolysis (80% AcOH, 20°, 8-15 min, 100% yield, or 3% trichloroacetic acid). It can be cleaved under neutral conditions with ZnBrj, thus reducing the extent of the often troublesome depurination of A -6-benzyloxy-adenine residues during deprotection. Conditions which remove the pixyl group also partially cleave the THP group (t,/2 for THP at 2 -OH of ribonucleoside = 560 s in 3% Cl2CHC02H/CH2Cl2). ... 

The adamantoate ester is formed selectively from a primary hydroxyl group (e.g., from the 5 -OH in a ribonucleoside) by reaction with adamantoyl chloride, Pyr (20°, 16 h). It is cleaved by alkaline hydrolysis (0.25 N NaOH, 20 min), but is stable to milder alkaline hydrolysis (e.g., NH3, MeOH), conditions that cleave an acetate ester. ... 

TsOH, MeOH, 25°, 5 h. These conditions failed to cleave the acetonide of a 2, 3 -ribonucleoside. ... 

FIGURE 11.11 The common ribonucleosides—cytidine, uridine, adenosine, and guanosine. Also, inosine drawn in anti conformation. 

The Cee group was developed for the protection of the 2 -hydroxyl group of ribonucleosides. 

Add 0.25 ml of DMF (./V,iV-dimethylformamide) and 0.25 ml of TRI-SIL TBT reagent to the sample in a screw-cap septum vial. If TRI-SIL TBT reagent is not readily available, add 0.25 ml of acetonitrile and 0.25 ml of BSTFA reagent instead. Heat at 60° for at least 1 hour for ribonucleosides or for a minimum of 3 hours for deoxyribo-nucleosides. After cooling to room temperature, inject 1-2 /a 1 of the reaction mixture directly into the GC. The resulting derivatives have been reported to be stable for weeks if capped tightly and refrigerated.1... 

Aminoimidazole-4-carboxamide ribonucleoside (also known as AICA riboside or AICAR). An adenosine analogue that is taken up into cells by adenosine transporters and converted by adenosine kinase to the monophosphorylated nucleotide form, ZMP. ZMP is an analogue of AMP that activates the AMP-activated protein kinase (AMPK), for which acadesine or AICAR can be used as a pharmacological activator. 

Henceforward, the chapter focuses on problems closely connected with the chemistry of ribonucleotide 46 and ribonucleoside 47. The official numbering of the atoms in these molecules is recalled in formulas 46, 47. The common abbreviations, AIR and AIRs respectively, are used for the ribotide and the riboside. 

N, /V-dimethylformamide.60 The sugars were isolated on a column of Dowex-50 X8 in the calcium form.6 Both d-(1-i3C)- and D-(2-l3C)-ribose are now commercially available. These sugars allowed the preparation of samples of AIRs labeled with 13C either on C-T or on C-2 In conclusion, four ribonucleosides are now available practically fully labeled at a single position.58... 

Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, Ramesh M, Chu CK, Jordan R, Shi J, Rachakonda S, Watanabe KA, Otto MJ, Schinazi RF (2003b) Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture, Antimicrob Agents Chemother 47 244-254... 

The 2 -C-methyl-substituted ribonucleosides 2 -C-methyladenosine and -guanosine were also found to inhibit the replication of flaviviruses other than HCV, such as bovine viral diarrhea virus (BVDV), yellow fever virus, and West Nile virus (Mighaccio et al. 2003). Other 2 -C-methylribonucleosides such as P-D-2 -deoxy-2 -lluoro-2 -C-methylcytidine (PSl-6130), however, showed little if any activity against BVDV, West Nile virus, or yellow fever virus (Stuyver et al. 2006). 

Although it was proposed that inhibition of HCMV DNA maturation by the benzimidazole ribonucleoside BDCRB is mediated through the UL89 gene product, and resistance to TCRB maps to the two ORFs UL89 and UL56, there was no cross-resistance of an HCMV AD 169 sulphonamide-resistant strain to BDCRB (Reefschlaeger et al. 1999). 

Underwood M, Harvey R, Stanat S, Hemphill M, Miller T, Drach J, Townsend L, Biron K (1998) Inhibition of human cytomegalovirus DNA maturation by a benzimidazole ribonucleoside is mediated through the UL89 gene product. J Virol 72 717-725 Van Maele B, Debyser Z (2005) HlV-1 integration an interplay between HIV-1 integrase, cellular, and viral proteins. AIDS Rev 7 26 3... 

Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J Biol Chem 278 49164 9170... 

The reduction of ribonucleoside triphosphates by various dithiols which are capable of intramolecular cyclization on oxidation (dihydrolipoate, dithioerythritol, dithiothreitol) yields 2 -deoxyribonucleoside triphosphates. These reactions also require 5-deoxyadenosylcorrinoids. 

Conversion of purines, their ribonucleosides, and their deoxyribonucleosides to mononucleotides involves so-called salvage reactions that require far less energy than de novo synthesis. The more important mechanism involves phosphoribosylation by PRPP (structure II, Figure 34-2) of a free purine (Pu) to form a purine 5 -mononucleotide (Pu-RP). 

REDUCTION OF RIBONUCLEOSIDE DIPHOSPHATES FORMS DEOXYRIBONUCLEOSIDE DIPHOSPHATES... 

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

Figure 34-5. Reduction of ribonucleoside diphosphates to 2 -deoxyribonucleoside diphosphates.

Template binding RNA polymerase (RNAP) binds to DNA and locates a promoter (P) melts the two DNA strands to form a preinitiation complex (PIQ. (2) Chain initiation RNAP holoenzyme (core + one of multiple sigma factors) catalyzes the coupling of the first base (usually ATP or GTP) to a second ribonucleoside triphosphate to form a dinucleotide. (3) Chain elongation Successive residues are added to the 3 -OH terminus of the nascent RNA molecule. (4) Chain termination and release The completed RNA chain and RNAP are released from the template. The RNAP holoenzyme re-forms, finds a promoter, and the cycle is repeated. 

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