2'-Spiro ribo- and arabinonucleosides

synthesis, molecular modelling and incorporation into oligodeoxynucleotides

B.R. Babu, L. Keinicke, M. Petersen, C. Nielsen, J. Wengel

Publikation: Bidrag til tidsskriftTidsskriftartikelForskning

Resumé

We have synthesized four conformationally restricted bicyclic 2′-spiro nucleosides via 2′-C-allyl nucleosides as key intermediates. The ribo-configured 2′-spironucleosides 9b and 14b were obtained by a convergent strategy starting from 2-ketofuranose 1 whereas the arabino-configured 2′-spironucleosides 21 and 27 were obtained by a linear strategy with a 2′-ketouridine derivative as starting material. The furanose ring of 9b/14b adopts N-type conformations whereas the furanose ring of 21/27 exists as an N⇄S equilibrium. These compounds showed no anti-HIV-1 activity or cytotoxicity. Incorporation of the four 2′-spironucleosides (as monomers X4 and X5) into oligodeoxynucleotides was accomplished using the phosphoramidite approach on an automated DNA synthesizer. Irrespective of monomeric configuration, hybridization studies revealed that these 2′-spironucleotide monomers (X4 and X5) induce decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes. Molecular modelling indicated that steric constraints are a possible reason for the lowered binding affinities of the modified oligodeoxynucleotides towards complementary single-stranded DNA and single-stranded RNA complements.

OriginalsprogEngelsk
TidsskriftOrganic & Biomolecular Chemistry
Vol/bind2003
Udgave nummer1
Sider (fra-til)3514-3526
ISSN1477-0520
DOI
StatusUdgivet - 2003

Fingeraftryk

Arabinonucleosides
Molecular modeling
Oligodeoxyribonucleotides
DNA
Nucleosides
Monomers
RNA
Single-Stranded DNA
Cytotoxicity
Conformations
Derivatives

Citer dette

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title = "2'-Spiro ribo- and arabinonucleosides: synthesis, molecular modelling and incorporation into oligodeoxynucleotides",
abstract = "We have synthesized four conformationally restricted bicyclic 2′-spiro nucleosides via 2′-C-allyl nucleosides as key intermediates. The ribo-configured 2′-spironucleosides 9b and 14b were obtained by a convergent strategy starting from 2-ketofuranose 1 whereas the arabino-configured 2′-spironucleosides 21 and 27 were obtained by a linear strategy with a 2′-ketouridine derivative as starting material. The furanose ring of 9b/14b adopts N-type conformations whereas the furanose ring of 21/27 exists as an N⇄S equilibrium. These compounds showed no anti-HIV-1 activity or cytotoxicity. Incorporation of the four 2′-spironucleosides (as monomers X4 and X5) into oligodeoxynucleotides was accomplished using the phosphoramidite approach on an automated DNA synthesizer. Irrespective of monomeric configuration, hybridization studies revealed that these 2′-spironucleotide monomers (X4 and X5) induce decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes. Molecular modelling indicated that steric constraints are a possible reason for the lowered binding affinities of the modified oligodeoxynucleotides towards complementary single-stranded DNA and single-stranded RNA complements.",
author = "B.R. Babu and L. Keinicke and M. Petersen and C. Nielsen and J. Wengel",
year = "2003",
doi = "10.1039/B306354B",
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pages = "3514--3526",
journal = "Organic & Biomolecular Chemistry",
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2'-Spiro ribo- and arabinonucleosides : synthesis, molecular modelling and incorporation into oligodeoxynucleotides. / Babu, B.R.; Keinicke, L.; Petersen, M.; Nielsen, C.; Wengel, J.

I: Organic & Biomolecular Chemistry, Bind 2003, Nr. 1, 2003, s. 3514-3526.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskning

TY - JOUR

T1 - 2'-Spiro ribo- and arabinonucleosides

T2 - synthesis, molecular modelling and incorporation into oligodeoxynucleotides

AU - Babu, B.R.

AU - Keinicke, L.

AU - Petersen, M.

AU - Nielsen, C.

AU - Wengel, J.

PY - 2003

Y1 - 2003

N2 - We have synthesized four conformationally restricted bicyclic 2′-spiro nucleosides via 2′-C-allyl nucleosides as key intermediates. The ribo-configured 2′-spironucleosides 9b and 14b were obtained by a convergent strategy starting from 2-ketofuranose 1 whereas the arabino-configured 2′-spironucleosides 21 and 27 were obtained by a linear strategy with a 2′-ketouridine derivative as starting material. The furanose ring of 9b/14b adopts N-type conformations whereas the furanose ring of 21/27 exists as an N⇄S equilibrium. These compounds showed no anti-HIV-1 activity or cytotoxicity. Incorporation of the four 2′-spironucleosides (as monomers X4 and X5) into oligodeoxynucleotides was accomplished using the phosphoramidite approach on an automated DNA synthesizer. Irrespective of monomeric configuration, hybridization studies revealed that these 2′-spironucleotide monomers (X4 and X5) induce decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes. Molecular modelling indicated that steric constraints are a possible reason for the lowered binding affinities of the modified oligodeoxynucleotides towards complementary single-stranded DNA and single-stranded RNA complements.

AB - We have synthesized four conformationally restricted bicyclic 2′-spiro nucleosides via 2′-C-allyl nucleosides as key intermediates. The ribo-configured 2′-spironucleosides 9b and 14b were obtained by a convergent strategy starting from 2-ketofuranose 1 whereas the arabino-configured 2′-spironucleosides 21 and 27 were obtained by a linear strategy with a 2′-ketouridine derivative as starting material. The furanose ring of 9b/14b adopts N-type conformations whereas the furanose ring of 21/27 exists as an N⇄S equilibrium. These compounds showed no anti-HIV-1 activity or cytotoxicity. Incorporation of the four 2′-spironucleosides (as monomers X4 and X5) into oligodeoxynucleotides was accomplished using the phosphoramidite approach on an automated DNA synthesizer. Irrespective of monomeric configuration, hybridization studies revealed that these 2′-spironucleotide monomers (X4 and X5) induce decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes. Molecular modelling indicated that steric constraints are a possible reason for the lowered binding affinities of the modified oligodeoxynucleotides towards complementary single-stranded DNA and single-stranded RNA complements.

U2 - 10.1039/B306354B

DO - 10.1039/B306354B

M3 - Journal article

VL - 2003

SP - 3514

EP - 3526

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

SN - 1477-0520

IS - 1

ER -