- The N-7 regioisomer of 2-chloro-2'-deoxyadenosine: synthesis, crystal structure, conformation, and stability
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The nucleoside 6-amino-2-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-purine 7 is readily accessible in two steps from 2,6-dichloropurine.The crystal structure of this unusual nucleoside reveals a bifurcated intramolecular hydrogen bond from the amino group to the O-5' with a weaker branch to the O-4' which imposes a syn glycosidic torsion angle: χ=67.0 deg.Semi-empirical calculations using AM1 parameters and optimisation of atomic co-ordinates derived from the crystal structure of 7 suggest that the molecule can adopt either anti or syn conformations with a slight preference for anti by 0.4 kcal mol-1 in heat of formation (ΔHf).NOE experiments in (CD3)2SO solution support the theoretical results indicating the presence of both syn and anti conformations and that the anti population is marginally favoured.The antileukaemic agent 2-chloro-2'-deoxyadenosine (6), the N-9 regioisomer of 7, was shown to be 9.6 kcal mol-1 more stable than 7.The increased stability of 6 over 7 seems attributable mainly to the relative stability of the aglycon tautomers 8 and 9, the energy difference between thase being 6.7 kcal mol-1 in favour of the 9H tautomer 8.Likewise, removal of the 2-chloro substituent has little effect on the tautomerism. Keywords: N-7 nucleoside; X-ray structure; semi-empirical; Conformation; NOE
- Worthington, Victoria L.,Fraser, William,Schwalbe, Carl H.
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- Synthesis and in vitro antiviral activities of [(dihydrofuran-2-yl)oxy]methyl-phosphonate nucleosides with 2-substituted adenine as base
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Abstract The synthesis of [(2′,5′-dihydrofuran-2-yl)oxy]methyl-phosphonate nucleosides with a 2-substituted adenine base moiety starting from 2-deoxy-3,5-bis-O-(4-methylbenzoyl)-α-L-ribofuranosyl chloride and 2,6-dichloropurine is described. The key step
- Liu, Fei,Liu, Yingju,Xu, Rui-Gang,Dai, Guifu,Zhao, Liu-Xi,Wang, Yafeng,Liu, Hong-Min,Liu, Feng-Wu,Pannecouque, Christophe,Herdewijn, Piet
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- A concise synthesis of isoguanine 2'-deoxyriboside and its adenine-like triplex formation when incorporated into DNA
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A concise synthesis of 2'-deoxyisoguanosine is achieved whereby 2,6-dichloropurine is glycosylated using the Hoffer sugar to give a pair of beta-configured nucleoside N9/N7 regioisomers that are aminated using methanolic ammonia with concomitant deprotection of the sugar. Following chromatographic separation, pure 2-chloro-2'-deoxyadenosine was isolated as a single isomer. Displacement of the C2 chlorine atom using sodium benzyloxide, followed by hydrogenolysis of the benzyl group, gives 2'-deoxyisoguanosine. Isoguanine was incorporated into DNA by solid supported synthesis using the suitably protected 2-allyloxy-2'-deoxyadenosine phosphoramidite with the allyl group being removed post-oligomerisation under Noyori conditions. DNA melting studies showed isoguanine to exhibit adenine-like triplex formation.
- Walsh, Andrew J.,Schwalbe, Carl H.,Fraser, William
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- Substituted purines and oligonucleotide cross-linking
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This invention is directed to novel purine-based compounds for inclusion into oligonucleotides. The compounds of the invention, when incorporated into oligonucleotides are especially useful as "antisense" agents--agents that are capable of specific hybrid
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- Oligonucleotides containing N-2 substituted purines
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This invention presents novel purine-based compounds for inclusion into oligonucleotides. The compounds of the invention, when incorporated into oligonucleotides are especially useful as "antisense" agents--agents that are capable of specific hybridization with a nucleotide sequence of an RNA. Oligonucleotides are used for a variety of therapeutic and diagnostic purposes, such as treating diseases, regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of antisense interactions with such RNA, diagnosing diseases, modulating the production of proteins, and cleaving RNA in site specific fashions. The compounds of the invention include novel heterocyclic bases, nucleosides, and nucleotides. When incorporated into oligonucleotides, the compounds of the invention can be useful for modulating the activity of RNA.
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- Method for the production of 2'-deoxyadenosine compounds
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A method that is direct and stereospecific is provided for the production of 2'-deoxyadenosine derivatives and related analogs. The method comprises glycosylation of the sodium salt of 2,6-dichloropurine or 6-chloropurine and ammonolysis of the glycosylat
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- Synthesis of 2'-Deoxytubercidin, 2'-Deoxyadenosine, and Related 2'-Deoxynucleosides via a Novel Direct Stereospecific Sodium Salt Glycosylation Procedure
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A general and stereospecific synthesis has been developed for the direct preparation of 2'-deoxy-β-D-ribofuranosylpurine analogues including 2'-deoxyadenosine derivatives.The reaction of the sodium salt of 4-chloropyrrolopyrimidine (4) or 2,4-dichloropyrrolopyrimidine (1) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose (25) provided the corresponding N-1,2'-deoxy-β-D-ribofuranosyl blocked derivatives (5 and 2) which, on ammonolysis, gave 2'-deoxytubercidin (6) and 2-chloro-2'-deoxytubercidin (3), respectively, in good yield.This glycosylation also readily proceeds in the presence of a 2-methylthio group.Application of this glycosylation procedure to 4,6-dichloroimidazopyridine (10), 6-chloropurine (16), 2,6-dichloropurine (13), and 4-chloropyrazolopyrimidine (19) gave 2-chloro-2'-deoxy-3-deazaadenosine (12), 2-'-deoxyadenosine (18), 2-chloro-2'-deoxyadenosine (15), and 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrazolopyrimidine (21), respectively.Similarly, glycosylation and ammonolysis of 4,6-dichloro-1H-pyrrolopyridine (22) gave 4,6-dichloro-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyridine (24).This stereospecific attachment of the 2-deoxy-β-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C-1 carbon of 25.
- Kazimierczuk, Zygmunt,Cottam, Howard B.,Revankar, Ganapathi R.,Robins, Roland K.
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p. 6379 - 6382
(2007/10/02)
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