Synthesis and hydrolytic stability of the α and β anomers of 4′-thio-2′-deoxyuridine and their 5-substituted analogs. Competition between the acid-catalysed depyrimidination and isomerisation to a 5-thiopyranoside nucleoside

Otter, G. P.; Elzagheid, Mohamed I.; Jones, Garry D.; MacCulloch, Alasdair; Walker, Richard; Oivanen, Mikko; Klika, Karel D.

doi:10.1039/a806276e

Cited by 8 publications

(3 citation statements)

References 13 publications

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“…2Ј-Deoxypseudouridine nucleotide was made as previously described (31), converted into its 5Ј-dimethoxytrityl (DMT) derivative, and phosphitylated to generate the 3Ј-phosphoramidite (G.W., unpublished results). Synthesis of 4Ј-thio-2Ј-deoxyuridine nucleotide was as previously described (32). A DMT group was added to the 5Ј position and the molecule converted to the 3Ј-phosphoramidite.…”

Section: Methodsmentioning

confidence: 99%

Uracil-DNA glycosylase–DNA substrate and product structures: Conformational strain promotes catalytic efficiency by coupled stereoelectronic effects

Parikh

Walcher

Jones

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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257

356

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Enzymatic transformations of macromolecular substrates such as DNA repair enzyme͞DNA transformations are commonly interpreted primarily by active-site functional-group chemistry that ignores their extensive interfaces. Yet human uracil-DNA glycosylase (UDG), an archetypical enzyme that initiates DNA base-excision repair, efficiently excises the damaged base uracil resulting from cytosine deamination even when active-site functional groups are deleted by mutagenesis. The 1.8-Å resolution substrate analogue and 2.0-Å resolution cleaved product cocrystal structures of UDG bound to double-stranded DNA suggest enzyme-DNA substrate-binding energy from the macromolecular interface is funneled into catalytic power at the active site. The architecturally stabilized closing of UDG enforces distortions of the uracil and deoxyribose in the flipped-out nucleotide substrate that are relieved by glycosylic bond cleavage in the product complex. This experimentally defined substrate stereochemistry implies the enzyme alters the orientation of three orthogonal electron orbitals to favor electron transpositions for glycosylic bond cleavage. By revealing the coupling of this anomeric effect to a delocalization of the glycosylic bond electrons into the uracil aromatic system, this structurally implicated mechanism resolves apparent paradoxes concerning the transpositions of electrons among orthogonal orbitals and the retention of catalytic efficiency despite mutational removal of active-site functional groups. These UDG͞DNA structures and their implied dissociative excision chemistry suggest biology favors a chemistry for base-excision repair initiation that optimizes pathway coordination by product binding to avoid the release of cytotoxic and mutagenic intermediates. Similar excision chemistry may apply to other biological reaction pathways requiring the coordination of complex multistep chemical transformations.

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Section: Methodsmentioning

confidence: 99%

Uracil-DNA glycosylase–DNA substrate and product structures: Conformational strain promotes catalytic efficiency by coupled stereoelectronic effects

Parikh

Walcher

Jones

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

257

356

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“…The same results were obtained even when BCl 3 /CH 2 Cl 2 employed as the deprotecting agents. Since this kind of reaction was not encountered in the case of 2'-deoxy-2'-Cmethylene-4'-thiocytidine [34], it can be safely assumed that strong electronegative difluoro substituents played a major role in the formation of elimination product under strongly acidic conditions. In order to avoid the formation of elimination product, the protecting group of the glycosyl donor was changed to benzoyl group.…”

Section: Following Is a Brief Account Of Synthesis (Scheme 3-22)mentioning

confidence: 98%

“…Otter et al[34] studied the course of degradation of 3-8 and 3-49 in aqueous acid. The acid catalyzed cleavage of N-glycosidic bond of the compounds was found to be in competition with isomerization of 4'-thionucleosides to their L…”

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confidence: 99%

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

Gunaga¹,

Moon²,

Choi³

et al. 2004

CMC

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The classical 4'-oxonucleoside analogs exhibit interesting biological activities such as antibiotic, antiviral and antitumor, which are believed to be the result of inhibition of the viral or cellular DNA or RNA polymerase after being converted to their corresponding 5'-triphosphates. However, the activity of 4'-oxonucleosides were limited by their susceptibility to degradation by nucleoside phosphorylases or acid hydrolysis. This aspect called for the chemical modification of the carbohydrate portion. This compulsion led to two kinds of strategies; (1) replacement of the 4'-oxygen by the methylene group - carbocyclic nucleosides; (2) replacement of the 4' oxygen by sulphur-4'-thionucleosides. This group has also conferred the resistance to the nucleoside cleavage. Although, there were some pioneering work on 4'-thionucleosides in 1960s and 1970s, the interest in this group of compounds was rekindled by the antiviral activities of 2'-deoxy-4'-thionucleosides reported independently by Secrist et al. and Walker et al. Subsequent contributions by the other authors, enhanced its standing as an important class of antiviral agents. Following is a reasonably exhaustive account of this class of compounds reported after 1990.

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Synthesis and Structural Elucidation of 2′-Deoxy-4′-thio-L-threo-pentofuranosylpyrimidine and -purine Nucleosides

et al. 2001

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Synthesis and hydrolytic stability of the α and β anomers of 4′-thio-2′-deoxyuridine and their 5-substituted analogs. Competition between the acid-catalysed depyrimidination and isomerisation to a 5-thiopyranoside nucleoside

Cited by 8 publications

References 13 publications

Uracil-DNA glycosylase–DNA substrate and product structures: Conformational strain promotes catalytic efficiency by coupled stereoelectronic effects

Uracil-DNA glycosylase–DNA substrate and product structures: Conformational strain promotes catalytic efficiency by coupled stereoelectronic effects

Recent Advances in 4-Thionucleosides as Potential Antiviral and Antitumor Agents

Synthesis and Structural Elucidation of 2′-Deoxy-4′-thio-L-threo-pentofuranosylpyrimidine and -purine Nucleosides

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