Nucleoside dimers

Nucleophilic alkylation, C=0, C=N, and enones, 9, 192 Nucleophilic substitutions Sn2 processes, 9, 520, 9, 5249, 548-549 SnI processes, 10, 684 Sn2 processes, 10, 684 with titanium alkoxide complexes, 4, 273 Nucleoside dimers, via cross metathesis, 11, 194 Nucleoside kinases, in medicinal chemistry, 12, 458 Nucleosides, iodinated, into zinc reagents, 9, 82-83... 

Stromberg has reported a detailed kinetic study of the pivaloyl chloride-promoted nucleoside TZ-phosphonate condensation step with a suitably protected nucleoside in the presence of differently substituted pyridines. He also investigated the stability of /Z-phosphonate nucleosidic dimers under various organic and aqueous basic conditions. Strong bases such as DBU and fluoride ions cleaved the dinucleoside ZZ-phosphonates rapidly, as also did a combination of protic solvent and a base. ... 

Nucleoside dimers linked by the butadiynediyi group were prepared by A. Burger et al. using the Eglinton modification of the Giaser coupiing via dimerization of 3 -C-ethynyl nucleosides. ... 

Jung, F., Burger, A., Biellmann, J.-F. Synthesis of Nucleoside Dimers Bridged on Ribose with a Butadiynyl Group. Org. Lett. 2003, 5, 383-385. 

Silnikov described a synthetic route to prepare over fourty 5 -triphosphate dinucleotides with modified carbohydrate-phosphate backbones with the general structure shown [65]. This route employed a combination of solution phase synthesis of the nucleoside dimers followed by the introduction of the triphosphate moiety. The dimers were synthesised from the partially protected nucleoside and 3 -0-/)-chlorophenyl-nucleoside phosphate diester in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride and A -Me-imidazole in pyridine. The pyrophosphate was introduced in a stepwise manner by initial deprotection of the primary alcohol followed by reaction with phosphorus oxychloride in pyridine with subsequent addition of the tetrabutylammonium salt of inorganic pyrophosphate in acetonitrile. 

Peoc h, D. et al.. Synthesis of 2 -substituted MMl linked nucleosidic dimers an optimization study in search of high affinity ohgonucleotides for use in antisense constructs. Nucleosides Nucleotides Nucleic Acids, 23,411,2004. 

The potential therapeutic applications of antisense ONs have rekindled the interest of researchers, including those at ISIS, in the development of better backbones for incorporation into ONs (Table 1). Comprehensive reviews of antisense ONs have been published, and here we present major developments from our group and others. Furthermore, this account is limited to the synthesis of oligonucleosides with a four-atom linker connecting the two pentofuranosyl moieties of a nucleoside dimer.I" In each section we describe a different type of backbone linkage. 

J-J. Vasseur, F. Debart, Y.S. Sanghvi, and P.D. Cook, Oligonucleotides synthesis of a novel methylhydroxylamine linked nucleoside dimer and its incorporation into antisense sequences, J. Am. Chem. Soc. 114 4006 (1992). 

In aqueous solution, caffeine associates to form at least a dimer and probably a polymer 12 the molecules are arranged in a stack.13 Caffeine will also associate with purines and pyrimidines either as the free bases or as their nucleosides.13 Caffeine crystallizes from water as a monohydrate [9],... 

In the reaction of di-(5 -0-monomethoxytrityhmdine-3 -/ -nitrophenylethyl)-pyro-phosphate with a 5 -OH nucleoside component, simultaneous addition of quinoline-8-sulfochloride and 3-nitro-1,2,4-triazole is recommended to obtain a high yield of the fully protected dimer. 1521... 

The HPLC-MS/MS assay was also successfully applied to the measurement of UV-induced dimeric pyrimidine photoproducts [123, 124]. The latter lesions were released from DNA as modified dinucleoside monophosphates due to resistance of the intra-dimer phosphodiester group to the exonuclease activity during the hydrolysis step [125, 126]. The hydrolyzed photoproducts exhibit mass spectrometry and chromatographic features that allow simultaneous quantification of the three main classes of photolesions, namely cyclobutane dimers, (6-4) photoproducts, and Dewar valence isomers, for each of the four possible bipyrimidine sequences. It may be added that these analyses are coupled to UV detection of normal nucleosides in order to correct for the amount of DNA in the sample and obtain a precise ratio of oxidized bases or dimeric photoproducts to normal nucleosides. 

In previous studies performed with similar heterodinucleoside phosphate dimers composed of the antivirally active nucleosides AZT, ddC and... 

The effect of phase upon the monomer-dimer equilibrium is pronounced. The quantum yields for dimer formation in liquid-aerated water solution are low (from zero for thymine to 10"2 for other pyrimidines) but the quantum yields for dimer formation in frozen aqueous solutions or in single crystals are much higher (reaching unity in frozen water solution for thymine). The quantum yields for monomerization are uniformly high and are about the same in solution or in solid phase. The net result of this phase effect is that even at optimum wavelengths for dimer formation, the yields of dimers are low in solution and high in solid phases, for all the single bases, nucleosides, or nucleotides. 

The crystal structure of [Cd(GlyGly)(Im)Cl] has been reported72 and shown to involve dimeric units with a distorted octahedral geometry about each metal atom this complex has also been studied in a 13C NMR investigation of a range of nucleoside and peptide complexes of cadmium(II).430... 

The action of venom exonuclease is also blocked by thymine dimers produced as a result of UV irradiation of DNA at 280 nm. Setlow et al. (66) subjected irradiated DNA to exhaustive digestion by venom exonuclease. They isolated and identified the products of the reaction, which were composed of large amounts of all four 5 -mononucleotides and of small amounts of trinucleotides of the type d-pNpTpT where N was any of four common nucleosides and TpT was the irradiation-induced dimer of thymidine. These trinucleotides were totally resistant to further digestion with venom exonuclease but became partially susceptible after UV irradiation at 240 nm, known to reverse dimerization. The authors picture the action of venom exonuclease as proceeding linearly from the internal bond one base beyond the dimer. From there on conventional hydrolysis is resumed until the next block. This experiment touches upon one of the most pressing problems connected with venom exonuclease. Is the endonucleolytic activity an intrinsic property of the enzyme ... 

The first result is that pyrimidine nucleosides do not give template polymerizations under the conditions tried. This is attributed to the inability of pyrimidine nucleosides to stack on the poly A or poly G template. It is possible that early template polymerizations used dimers, trimers, etc. which may stack, or that there may be conditions not yet found which... 

Olefins are also susceptible to cycloaddition reactions (Fig 105) (150). In particular, some olefin-containing APIs can dimerize with another molecule of API to form a 2+2 cycloaddition product under photo conditions (151). A classic example of such a 2+2 cycloaddition catalyzed by UV radiation is that of the nucleoside thymidine (Fig. 106) (152,153). These reactions are proposed to go through more than one mechanism concerted, diradical, electron transfer, and radical ion pairs. 

The studies of Levene and LaForge60 on the nitration of uridine have since been re-investigated. It had been reported, several decades ago, that treatment of uridine with nitric acid produced a Nitro-Uridin-Carbon-saure which was stated to be a dimer containing an anhydro typeof linkage (positions unspecified) between two nucleoside residues.60 According to an abstract,269 this compound has now been identified as the monomeric 5-ni-tro-l-(/8-D-ribosyluronic acid)uracil (CXXII) this was converted to the isopropyl ester and the 2,3-O-isopropylidene acetal thereof. Nitration of the pyrimidine moiety of uridine without oxidation of the 4-(hydroxy-... 

In the situation with 1,2-diols, such as depicted in Scheme 4.1b, where the oxygens of the V02 grouping are not incorporated into the core, the dimeric structure of the complex is highly favored in aqueous solution. For a nucleoside complex, the VO bond of the V02 moiety are 1.625 lengths and 1.626 A, whereas the individual VO bonds of the core are 2.036 A and 1.983 A in length [3], Dimeric structures,... 

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