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. 2002 Dec 15;30(24):5485-96.
doi: 10.1093/nar/gkf689.

Propynyl groups in duplex DNA: stability of base pairs incorporating 7-substituted 8-aza-7-deazapurines or 5-substituted pyrimidines

Junlin He  1 , Frank Seela
Affiliations

Propynyl groups in duplex DNA: stability of base pairs incorporating 7-substituted 8-aza-7-deazapurines or 5-substituted pyrimidines

Junlin He et al. Nucleic Acids Res. .

Abstract

Oligonucleotides incorporating the 7-propynyl derivatives of 8-aza-7-deaza-2'-deoxyguanosine (3b) and 8-aza-7-deaza-2'-deoxyadenosine (4b) were synthesized and their duplex stability was compared with those containing the 5-propynyl derivatives of 2'-deoxycytidine (1) and 2'-deoxyuridine (2). For this purpose phosphoramidites of the 8-aza- 7-deazapurine (pyrazolo[3,4-d]pyrimidine) nucleosides were prepared and employed in solid-phase synthesis. All propynyl nucleosides exert a positive effect on the DNA duplex stability because of the increased polarizability of the nucleobase and the hydrophobic character of the propynyl group. The propynyl residues introduced into the 7-position of the 8-aza-7-deazapurines are generally more stabilizing than those at the 5-position of the pyrimidine bases. The duplex stabilization of the propynyl derivative 4b was higher than for the bromo nucleoside 4c. The extraordinary stability of duplexes containing the 7-propynyl derivative of 8-aza-7- deazapurin-2,6-diamine (5b) is attributed to the formation of a third hydrogen bond, which is apparently not present in the base pair of the purin-2,6-diamine 2'-deoxyribonucleoside with dT.

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Figures

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Scheme 1.
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Scheme 1.
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Scheme 2. (i) and (ii) Propyne, Pd(0)(PPh3)4, CuI, Et3N, Ar, r.t., 18 h. (iii) (MeO)2TrCl, pyridine, r.t.; 3 h. (iv) 2-Cyanoethyl diisopropylphosphoramido chloridite, CH2Cl2, r.t., 30 min.
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Scheme 2. (i) and (ii) Propyne, Pd(0)(PPh3)4, CuI, Et3N, Ar, r.t., 18 h. (iii) (MeO)2TrCl, pyridine, r.t.; 3 h. (iv) 2-Cyanoethyl diisopropylphosphoramido chloridite, CH2Cl2, r.t., 30 min.
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Scheme 3. (i) and (ii) Phthaloylamidopropyne Pd(0)(PPh3)4, CuI, Et3N, Ar, r.t., 21 h. (iii) 2-Cyanoethyl diisopropylphosphoramido chloridite, CH2Cl2, r.t., 30 min.
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Scheme 3. (i) and (ii) Phthaloylamidopropyne Pd(0)(PPh3)4, CuI, Et3N, Ar, r.t., 21 h. (iii) 2-Cyanoethyl diisopropylphosphoramido chloridite, CH2Cl2, r.t., 30 min.
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Scheme 4. (i) N,N-Dimethylformamide dimethyl acetal in methanol, r.t. (ii) DMT-Cl, dry pyridine, 3 h at r.t. (iii) 2-Cyanoethyl diisopropylphosphoramido chloridite, diisopropylethylamine, CH2Cl2, 1 h, at r.t.
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Scheme 4. (i) N,N-Dimethylformamide dimethyl acetal in methanol, r.t. (ii) DMT-Cl, dry pyridine, 3 h at r.t. (iii) 2-Cyanoethyl diisopropylphosphoramido chloridite, diisopropylethylamine, CH2Cl2, 1 h, at r.t.
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Scheme 5.
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Scheme 5.
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Scheme 6.
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Scheme 6.
Figure 1
Figure 1
HPLC profile of enzymatic analysis of oligonucleotides 20 containing 3b (A), 24 containing 10c (B), 39 containing 5b (C), 34 containing 2 (D) by phosphodiesterase and alkaline phosphatase in 0.1 M Tris–HCl buffer (pH 8.3) at 37°C. Condition: reversed-phase HPLC at 260 nm on an RP-18 column (200 × 10 mm) with 100% B as the eluent, 0.7 ml/min (for composition of B, see Materials and Methods).
Figure 2
Figure 2
The CD spectra of oligonucleotides containing 1 and 3b (A), 4b (B) and 5b (C). Measured at 10°C in buffers as indicated in Tables 3–8.
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References

    1. Seela F. and Becher,G. (2001) Pyrazolo[3,4-d]pyrimidine nucleic acids: adjustment of dA–dT to dG–dC base pair stability. Nucleic Acids Res., 29, 2069–2078. - PMC - PubMed
    1. Boudou V., Kerremans,L., De Bouvere,B., Lescrinier,E., Schepers,G., Busson,R., Van Aerschot,A. and Herdewijn,P. (1999) Base pairing of anhydrohexitol nucleosides with 2,6-diaminopurine, 5-methylcytosine and uracil as base moiety. Nucleic Acids Res., 27, 1450–1456. - PMC - PubMed
    1. Seela F. and Becher,G. (1998) Synthesis of 7-halogenated 8-aza-7-deaza-2′-deoxy-guanosines and related pyrazolo[3,4-d]pyrimidine 2′-deoxyribonucleosides. Synthesis, 207–214.
    1. Seela F. and Steker,H. (1986) Synthesis of 2′-deoxyribofuranosides of 8-aza-7-deazaguanine and related pyrazolo[3,4-d]pyrimidines. Helv. Chim. Acta, 69, 1602–1613.
    1. Seela F., Winkeler,H.-D., Driller,H. and Menkhoff,S. (1984) Synthesis of 7-deaza-2′-deoxyguanosine by phase-transfer glycosylation and preparation of suitable derivatives for oligonucleotide synthesis. Nucleic Acids Res., 14, 245–246.

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