2,3-dideoxy-Nucleoside

Recent methods for the synthesis of nucleoside derivatives which have been tested for anti-HIV activity, or which, because of their structure, may be good candidates for testing are described. The nucleoside derivatives considered in this review are 3 -azido-2, 3 -dideoxynucleosides, 2, 3 -dideoxy-3 -fluoronucleosides, 2, 3 -dideoxy-3 -C-substituted nucleosides, 2, 3 -dideoxy-P-D-glycero-pent-2-enofuranosyl nucleosides, 2, 3 -dideoxynucleosides and carbocyclic, acyclic and C-nucleosides. Structure-activity relationships are also considered. 

Section 28 14 The nucleotide sequence of DNA can be determined by a technique m which a short section of single stranded DNA is allowed to produce its complement m the presence of dideoxy analogs of ATP TTP GTP and CTP DNA formation terminates when a dideoxy analog is incorporated into the growing polynucleotide chain A mixture of polynucleotides dif fermg from one another by an incremental nucleoside is produced and analyzed by electrophoresis From the observed sequence of the comple mentary chain the sequence of the original DNA is deduced... 

Phosphonylmethoxyethyl)adenine [106941-25-7] (PMEA, 65) (173), synthesized in 1987 (174), is foremost among the acycHc nucleoside analogues proven to be effective inhibitors of HIV-1 repHcation. The in vitro potency and selectivity of PMEA is comparable to the antiHIV-1 potency and selectivity of 2, 3 -dideoxy-adenosine (175). Although less potent than AZT in vitro PMEA, CgH22N 04P, is markedly more potent than AZT as an in vivo inhibitor of retrovims repHcation (176). In fact, PMEA has proven efficacious in the treatment of murine, feline, and simian retrovims infections in mice, cats, and monkeys, respectively. 

FIGURE 12.3 The chain termination or dideoxy method of DNA sequencing, (a) DNA polymerase reaction, (b) Structure of dideoxynucleotide. (c) Four reaction mixtures with nucleoside triphosphates plus one dideoxynucleoside triphosphate, (d) Electro-phoretogram. Note that the nucleotide sequence as read from the bottom to the top of the gel is the order of nucleotide addition carried out by DNA polymerase. 

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... 

Wang J, Jin Y, Rapp KL, Bennett M, Schinazi RF, Chu CK (2005) Synthesis, antiviral activity, and mechanism of drug resistance of d- and L-2, 3 -didehydro-2, 3 -dideoxy-2 -fluorocarbocycUc nucleosides, J Med Chem 48 3736-3748... 

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-... 

Much simpler fluorine-containing nucleosides, 855 and 856, were prepared " by the coupling method. 3 -Amino-3, 5 -dideoxy-5 -fluorothymi-... 

Deoxy-5 -fluoroadenosine (911) and the analogs 910, 912, 913 were prepared by coupling of 5-deoxy-5-fluoro-D-ribofuranose and 6-chloro-purine. 2, 5 -Dideoxy-5 -fluoroadenosine (914) was prepared through a displacement reaction of the corresponding 5 -0-tosyl precursor with fluoride (BU4NF in DMF). The carbocyclic nucleosides 915 and 916 have been prepared and their antiviral activities evaluated. 

Addition of a catalyst containing sulfuric acid and acetic anhydride to 3, 5 -di-0-acetylthymidine in acetonitrile results in an equilibrium mixture of a- and ]3-anomers that, after time, gave a substantial quantity of a diastereoisomeric mixture of fully acetylated open-chain nucleosides. These were of type 1.5 with 2 -deoxy and 4 -acetoxy substituents (93TL6779). Open-chain nucleoside was also obtained as well as the expected nucleoside when 5-nitrouracil was condensed with methyl-2,3-dideoxy-3-fluoro-5-0-(4-phenylbenzoyl)-]3-D-cryr/zro-pentofuranoside (94S516). 

Pyrimidine nucleoside hydrolase YeiK from E. coli in complex (PDB 3MKN) with l-(3,4-diaminophenyl)-l,4-dideoxy-l,4-imino-D-ribitol (175, 76 pM Scheme 48)... 

Purine and pyrimidine nucleosides of AZT (Zidovudine, 3 -azido-3 -deoxythymidine) with [RuO ] (from RuClj/K S O/aq. M KOH) gave l-((3-azido-2,3-dideoxy-P-D-eryf/tro-pentafuranosyl-5-uronic acid)-thymine (Fig. 2.11) [335]. 

Additional nucleoside analogues like the purine dideoxynucleosides lamivudine (3TC) and dideoxy-cytidine (ddC, zalcitabine) act in the same way as AZT. Resistance against these agents may show different patterns. They are generally less toxic than AZT. Adverse effects include diarrhoea and other gastrointestinal disturbances, headache, anxiety, restlessness and insomnia. Also hepatotoxicity can occur, probably because some of these drugs might have also some affinity for human DNA polymerases in the liver. 

N-Ribohydrolases have been found to be involved in novel pathways of purine salvage in protozoan parasites as well as in nucleic acid repair, and exhibit other interesting biological activities [178]. In order to investigate the molecular electrostatic potential surface of the enzyme from the trypanosome Crithidia fasci-culata, several l,4-dideoxy-l,4-imino-D-ribitol derivatives were synthesized as nucleoside analogues and their inhibitory powers were tested [179,180]. In the course of this work, l,4-dideoxy-l,4-imino-l(S)-phenyl-D-ribitol (97) was found to inhibit this enzyme with K 30 nmol/1. 

Allylic esters of fluoroacetic acid were used in the Ireland silyl ketene acetal rearrangement procedures by the Welch group at Albany [164]. For example, Eq. (53) shows a highly diastereoselective rearrangement which formed an early stage in syntheses of 2,3-dideoxy-2-fluoro-3-C-methyl pentose nucleosides [165, 166]. If a stereoselective synthesis of a functionalised monofluorocompound is... 

Treatment of the unsaturated C-nucleoside 69 with activated manganese dioxide afforded 2-(l,5-anhydro-2,6-dideoxy-L-m/thro-hex-l-eni-tol-l-yl-3-ulose)-8-nitro-u-triazolo[l,5-fl]pyridine (70) in 40% yield.13... 

The reduction of unsaturated-ketohexosyl purines has been thoroughly studied.52 53 In particular, in the case of the unsaturated 2 -keto-nucleosides 61a, 61b, and 63, a mechanism of the reduction by metal hydride was established53 by study of the n.m.r. spectra of the different deoxynucleosides obtained by the action of sodium borohydride in deu-terated solvents and of sodium borodeuteride in nondeuterated solvents. The reduction of both 7-(3-0-acetyl-4,6-dideoxy-L-g(i/cm>-hex-3-eno-pyranosyl-2-ulose)theophylline (61a) and its 6-chloropurine relative 61b in methanol led, respectively, to 7-(2-0-acetyl-4,6-dideoxy-/ -L-xi/fo-hexopyranosyl)theophylline (90a) and (2-0-acetyl-4,6-dideoxy-/ -L-xi/fo-hexopyranosyl)-6-chloropurine (90b) having OH-2 equatorial,... 

The first, in vivo study on the antitumor activity of ketonucleosides appeared14 in 1977. The action of l-(6-deoxy-2,3-0-isopropylidene-a-L-h/xo-hexopyranosyl-4-ulose)thymine (45) and of 7-(3-0-acetyl-4,6-dideoxy-/ -L-gfi/cero-hex-3-enopyranosyl-2-ulose)theophylline (61a) against LI 210 leukemia in mice was examined comparatively. From the results obtained, it was clear that the unsaturated ketohexosylpurine 61a was much more active than the ketohexosylpyrimidine 45, whereas the parent nucleosides (44 and 34a, respectively) were inactive under the same experimental conditions. 

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