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Volumn 52, Issue 39, 1996, Pages 12699-12722

6'-Carbon-substituted carbocyclic analogs of 2'-deoxyribonucleosides - Synthesis and effect on DNA/RNA duplex stability

Author keywords

[No Author keywords available]

Indexed keywords

CARBOCYCLIC NUCLEOSIDE; THYMIDINE DERIVATIVE;

EID: 0030599270     PISSN: 00404020     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4020(96)00755-7     Document Type: Article
Times cited : (18)

References (46)
  • 5
    • 0002037209 scopus 로고
    • Carbohydrate modifications in antisense research
    • ACS, Washington
    • 5. "Carbohydrate Modifications in Antisense Research", Sanghvi, Y. S.; Cook, P. D., eds., ACS Symposium Series, ACS, Washington, 1994.
    • (1994) ACS Symposium Series
    • Sanghvi, Y.S.1    Cook, P.D.2
  • 10
    • 85030273189 scopus 로고    scopus 로고
    • note
    • 10. The numbering system used for carbocyclic nucleoside analogs in ref. 11a is employed in the body text. In this nomenclature the carbon atom replacing the furanose ring oxygen of natural nucleosides is designated C-6′.
  • 17
    • 0012980002 scopus 로고
    • Our synthesis of (-)-2 is based on the separation of the diastereomeric (-)-ephedrine salts of tetrahydrophthalic acid monomethylester
    • b. Gais, H. J.; Lukas, K. L.; Ball, W. A.; Braun, S.; Lindner, H. J. Liebigs Ann. Chem. 1986, 687-716. Our synthesis of (-)-2 is based on the separation of the diastereomeric (-)-ephedrine salts of tetrahydrophthalic acid monomethylester.
    • (1986) Liebigs Ann. Chem. , pp. 687-716
    • Gais, H.J.1    Lukas, K.L.2    Ball, W.A.3    Braun, S.4    Lindner, H.J.5
  • 23
    • 85030278183 scopus 로고    scopus 로고
    • note
    • 3 and (C-4′)H, respectively. (equation presented) Strong NOE's were also detected between (C-6)H of the thymine base and (C-2′)H-β and (C-6′)H, respectively. Finally an NOE was observed between (C-1′)H and (C-2′)H-α, whereas none was detectable between (C-1′)H and (C-2′)H-β, clearly indicating a cis relationship between (C-1′)H and (C-2′)H-α.
  • 26
    • 85030272527 scopus 로고    scopus 로고
    • note
    • 3 solution was on the order of a few hours.
  • 28
    • 85030274030 scopus 로고    scopus 로고
    • note
    • 24. In principle, 14 can be isolated by flash chromatography on silica gel and in two separate experiments was obtained in 66% (7.25 g scale) and 46% (2.7 g scale) yield after chromatographic purification. However, as purificaton of 14 was always accompanied by the formation of 12 and several (unidentified) decomposition products (in a third experiment 14 could not be recovered intact from the column at all), the conversion of 12 into 16 without purification of intermediates proved to be the most efficient strategy for the prepartion of the latter compound. Upon standing at RT pure 14 slowly reverted to 12.
  • 29
    • 85030272271 scopus 로고    scopus 로고
    • note
    • 2OTBDMS also in 15, it was of much lower intensity than the one found in 17. In addition, a strong NOE between (C-4)H and (C-1)H was observed in 15, while this NOE was absent in 17.
  • 31
    • 84985516446 scopus 로고
    • b. The use of morpholine as allyl cation scavenger has been reported for the cleavage of allyl esters: Kunz, H.; Waldmann, H. Angew. Chem. Int. Ed. Engl. 1984, 23, 71-72.
    • (1984) Angew. Chem. Int. Ed. Engl. , vol.23 , pp. 71-72
    • Kunz, H.1    Waldmann, H.2
  • 32
    • 85030273956 scopus 로고    scopus 로고
    • note
    • 20 Regarding the configuration of the double bond in 20, this was not explicitly determined. However, based on data that we have obtained for related compounds the stereochemistry is likely to be as drawn.
  • 42
    • 85030278978 scopus 로고    scopus 로고
    • note
    • 34. For a comprehensive discussion of the concept of chimeric antisense oligonuceotides ("RNAse H window strategy") see: a. Ref. 4.
  • 44
    • 85030273235 scopus 로고    scopus 로고
    • note
    • 35. In in vitro experiments using 10% heat inactivated fetal calf serum as nuclease source 5′-TCCAGGTGTCCGtttC-3′ (t = 6′-α-methyl carbocyclic thymidine) was found to be 14 times more stable to degradation by 3′-exonucleases than the unmodified (phosphodiester based) parent oligonucleotide.


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