Parallel DNA containing pyrazolo[3,4-D]pyrimidine analogues of isoguanine

Article abstract of DOI:10.1081/NCN-100002537

The phosphoramidites of 8-aza-7-deaza-2′-deoxyisoguanosine (1a) and its bromo derivative lb as well as of 6-aza-2′-deoxyisocytidine and its 5-methyl derivative (3a,b) were synthesized. Parallel-stranded duplexes containing the nucleosides 1a,b show a sign

Full text of DOI:10.1081/NCN-100002537

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PARALLEL DNA CONTAINING PYRAZOLO[3,4-
D]PYRIMIDINE ANALOGUES OF ISOGUANINE
F. Seela a , R. Kröschel a & Y. He a
a Institut für Chemie, Universität Osnabrück , Laboratorium für Organische und
Bioorganische Chemie, Barbarastr. 7, Osnabrück, D-49076, Germany
Published online: 07 Feb 2007.
To cite this article: F. Seela , R. Kröschel & Y. He (2001) PARALLEL DNA CONTAINING PYRAZOLO[3,4-D]PYRIMIDINE
ANALOGUES OF ISOGUANINE, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1283-1286, DOI: 10.1081/NCN-100002537
To link to this article: http://dx.doi.org/10.1081/NCN-100002537
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1283–1286 (2001)
PARALLEL DNA CONTAINING
PYRAZOLO[3,4-D]PYRIMIDINE
ANALOGUES OF ISOGUANINE
F. Seela,∗ R. Kro¨schel, and Y. He
Laboratorium fu¨r Organische und Bioorganische Chemie,
Institut fu¨r Chemie, Universita¨t Osnabru¨ck, Barbarastr.
7, D-49076 Osnabru¨ck, Germany
ABSTRACT
The phosphoramidites of 8-aza-7-deaza-2ꢀ-deoxyisoguanosine (1a) and its
bromo derivative 1b as well as of 6-aza-2ꢀ-deoxyisocytidine and its 5-methyl
derivative (3a,b) were synthesized. Parallel-stranded duplexes containing the
nucleosides 1a,b show a significantly enhanced duplex stability compared to
those containing 2ꢀ-deoxyisoguanosine.
Parallel-stranded (ps) DNA is formed when the guanine-cytosine base pair
is replaced by isoguanine-cytosine and/or guanine-isocytosine pairs. This work re-
portsontheadjustmentofthelowerstabilityofparallelDNAtothatwithantiparallel
chain orientation and on the replacement of the acid-labile 2ꢀ-deoxyisoguanosine
(5) and 2ꢀ-deoxyisocytidine (6) by nucleoside analogues. For this purpose the nu-
cleosides 1a,b and 3a,b were synthesized. They were converted in their phospho-
ramidites 2a,b and 4a,b. Compounds 2a,b were employed in solid-phase
synthesis.
The nucleoside 1b was prepared by selective deamination of 2-amino-7-
bromo-8-aza-7-deaza-2ꢀ-deoxyadenosine (1) (7) with sodium nitrite/acetic acid.
Compound 1a – and even more 1b – are acid stable surrogates of 2ꢀ-deoxyis-
oguanosine (5). The latter shows a rather low glycosylic bond stability (2–4). The
∗ Corresponding author.
1283
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
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SEELA, KROSCHEL, AND HE
1284
Scheme 1.
2ꢀ-deoxyisocytidine (6) and its 5-methyl derivative are also acid labile; thus 6-aza-
2ꢀ-deoxyisocytidine (3a) and its 5-methyl derivative (3b) were synthesized as well
(5–9). The glycosylic bond stability of the nucleosides is shown in Table 1.
Oligonucleotides containing compounds 1a,b were synthesized using phos-
phoramidite chemistry. The N,N-dimethylaminomethylidene group was used for
the protection of the amino group of 1a (→ 8), the 2-oxo group was protected with
the diphenylcarbamoyl residue (→ 9). Tritylation and phosphitylation furnished
the phosphoramidite 2b. The building blocks of 4a,b were prepared in a sim-
ilar way. Solid-phase synthesis of oligonucleotides was performed on 1-µmole
scale using the phosphoramidites 2a,b. The coupling yield was always higher
than 97%.
According to Table 2 the replacement of dG by compound 1b results in a
significant enhancement of the Tm-values of self-complementary oligonucleotides
with overhanging nucleoside residues (4◦C/modification). The effect on the non
self-complementary duplexes is smaller (Table 2). In the case of the alternating
structures roughly 1/3 of the Tm-enhancement can be traced back to the overhangs
while the incorporation of the bromo derivative 1b contributes the other 2/3.
In the case of non self-complementary duplexes a smaller Tm increase (1.5◦C/-
modification) is observed. Obviously, bulky halogen atoms are well accommodated
Table 1. Half Lifes of 2ꢀ-Deoxyisoguanosine and 2ꢀ-Deoxyisocytidine
Analogues
Compound
0.1 N HCl
0.5 N HCl
τ [min]
iGd
25◦C
—
—
25◦C
40◦C
—
14
13
46
75
250
c7z8iGd (1a)
Br7c7z8iGd (1b)
z6iCd (3a)
m5z6iCd (3b)
—
40◦C
40◦C
—

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PARALLEL-STRANDED DNA
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Scheme 2.
Table 2. Tm-Values and Thermodynamic Data of Parallel-stranded Duplexes
Tm
ꢀH◦
[kcal/mol]
ꢀS◦
[cal/molK]
ꢀG◦
[kcal/mol]
Duplex
[◦C]
5ꢀ-d(1b-C-1b-C-1b-C) 11
57
41
33
44
43
47
−60
−47
−34
−85
−78
−82
−162
−128
−88
−10.5
5ꢀ-d(1b-C-1b-C-1b-C) 11
5ꢀ-d(1a-C-1a-C-1a-C) 1210
−7.8
−6.2
5ꢀ-d(1a-C-1a-C-1a-C) 12
5ꢀ-d(5-C-5-C-5-C) 1310
5ꢀ-d(5-C-5-C-5-C) 13
5ꢀ-d(T-iC-A-T-A-A-iC-T-5-5-A-T) 1411
5ꢀ-d(A-G-T-A-T-T-G-A-C-C-T-A) 15
5ꢀ-d(T-iC-A-T-A-A-iC-T-1a-1a-A-T) 16
5ꢀ-d(A-G-T-A-T-T-G-A-C-C-T-A) 15
5ꢀ-d(T-iC-A-T-A-A-iC-T-1b-1b-A-T) 17
5ꢀ-d(A-G-T-A-T-T-G-A-C-C-T-A) 15
−242
−209
−231
−10.3
−9.0
−10.4
a) Measured in 1 M NaCl, 0.1 M MgCl2, 60 mM sodiumcacodylate buffer, pH 7.0.
b) iCd = m5iCd.
in the grooves of parallel-stranded DNA which show an almost identical size. The
base pairs of 8-aza-7-deazaisoguanine-containing duplexes are represented by the
tridentate motifs I and II. Currently, we are investigating duplexes containing the
base pair motifs III and IV.
MOTIFS I-IV

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REFERENCES AND NOTES
1. Seela, F.; Becher, G.; Zulauf, M. Nucleosides & Nucleotides, 1999, 18, 1399–1400.
2. Seela, F.; Gabler, B.; Kazimierczuk, Z. Collect. Czech Chem. Commun. (Special Issue),
1993, 58, 170–173.
3. Seela, F.; Wei, C. Helv. Chim. Acta, 1997, 82, 73–85.
4. Sugyama, H.; Ikeda, S.; Saito, I. J.Am. Chem. Soc., 1996, 118, 9994–9995.
5. Sanghvi, Y. S.; Hoke, G. D.; Freier, S. M.; Zounes, M. C.; Gonzalez, C.; Cummins,
L.; Sasmor, H.; Cook, P. P. Nucleic Acids Res., 1993, 21, 3197–3203.
6. NMR-Data of 3a: δH [D6(DMSO)] 2.07, 2.57 (2 H, 2 m, 2ꢀ-H); 3.44 ( 2 H, m, 5ꢀ-H);
3.74 (1 H, m, 4ꢀ-H); 4.27 (1 H, m, 3ꢀ-H); 4.86 (1 H, t, J 5.4, 5ꢀ-OH); 5.26 (1 H, d, J
4.4, 3ꢀ-OH); 6.06 (1 H, t, J 6.3, 1ꢀ-H); 7.34 (1 H, s, 5-H); 7.46 (2 H, s, NH2).
7. Watanabe, K. A.; Reichman, U.; Chu, C. K.; Fox, J. J. 1978, Nucleic Acid Chemistry
(Tipson, R. S.; Townsend, L. B. Eds.) part 1, 273–277, J. Wiley and Sons, New York.
8. Kowollik, G.; Langen, P. J. Prakt. Chem., 1968, 37, 311–318.
9. Switzer, C. Y.; Moroney, S. E.; Benner, S. A. Biochemistry, 1993, 32, 10489–10496.
10. Seela, F.; Wei, C.; Melenewski, A.; He, Y.; Kro¨schel, R.; Feiling, E. Nucleosides &
Nucleotides, 1999, 18, 1543–1548.
11. Seela, F.; Wei, C. Helv. Chim. Acta, 1999, 82, 726–745.
12. NMR-Data of 8: δH[D6(DMSO)] 2.31, 2.77 (2 H, 2 m, 2ꢀ-H); 3.04 (2 H, m, 5ꢀ-H); 3.22,
3.27 (6 H, 2 m, 2 × NCH3); 3.68 (6 H, 2 m, 2 × CH3O); 3.93 (1 H, m, 4ꢀ-H); 4.50 (1 H,
t, J 4.9, 3ꢀ-H); 5.35 (1 H, d, J 4.9, 3ꢀ-OH-C(3ꢀ)); 6.51 (1 H, m, 1ꢀ-H); 6.49 − 7.45 (23
H, m, DPC + DMT); 8.87 (1 H, s, HC=N).

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