Nucleic Acids Research, Vol 25, Issue 10 1935-1942, Copyright © 1997 by Oxford University Press
DE Bergstrom, P Zhang and WT Johnson
The nucleoside analogs 1-(2'-deoxy-beta-D-ribofuranosyl)- 3- nitropyrrole
(9), 1-(2'-deoxy-beta-D-ribofuranosyl)-4-nitropyrazole (10),
1-(2'-deoxy-beta-D-ribofuranosyl)-4-nitroimidazole (11) and 1-(2'-
deoxy-beta-D-ribofuranosyl)-5-nitroindole (21) were incorporated into the
oligonucleotide 5'-d(CGCXAATTYGCG)-3'in the fourth position from the
5'-end. Procedures for synthesis of two of the nitroazole nucleosides, 10
and 11, were developed for this study. Each of the nitroazoles was
converted into a 3'-phosphoramidite for oligonucleotide synthesis by
conventional automated protocols. Four oligonucleotides were synthesized
for each modified nucleoside in order to obtain duplexes in which each of
the four natural bases was placed opposite (position 9) the nitroazole. In
order to assess the role of the nitro group on base stacking interaction,
sequences were also synthesized in which the fourth base was
1-(2'-deoxy-beta-D-ribofuranosyl)pyrazole. Corresponding sequences
containing an abasic site, as well as sequences containing inosine, were
synthesized for comparison. Thermal melting studies yielded T m values and
thermodynamic parameters. Each nucleoside analog displayed a unique pattern
of base pairing preferences. The least discriminating analog was
3-nitropyrrole, for which T m values differed by 5 degrees C and Delta G 25
degrees C ranged from -6.1 to -6.5 kcal/mol. 5-Nitroindole gave duplexes
with significantly higher thermal stability, with Tm values varying from
35.0 to 46.5 degrees C and -Delta G 25 degrees C ranging from 7.7 to 8.5
kcal/mol. Deoxyinosine (22), a natural analog which has found extensive use
as a universal nucleoside, is far less non-discriminating than any of the
nitroazole derivatives. Tm values ranged from 35.4 degrees C when paired
with G to 62.3 degrees C when paired with C. The significance of the nitro
substituent was determined by comparison of the base pairing properties of
a simple azole nucleoside, 1-(2'-deoxy- beta-D-ribofuranosyl)pyrazole (12).
The pyrazole-containing sequences melt at 10-20 degrees C lower than the
corresponding nitropyrazole- containing sequences. On average, the
pyrazole-containing sequences were equivalent in stability (average Delta G
= -4.8 kcal/mol) to the sequences containing an abasic site (average Delta
G = -4.7 kcal/mol).
ARTICLES
Comparison of the base pairing properties of a series of nitroazole nucleobase analogs in the oligodeoxyribonucleotide sequence 5'- d(CGCXAATTYGCG)-3'
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA. bergstrom@pharmacy.edu
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