Chemistry Reference
In-Depth Information
RNA. Molecular modelling suggested that the insertion of a three or more base
bulge into duplex DNA should induce a bend towards the major groove that sub-
sequently decreases the amount of helical twist at the bulge site.
101
Consequently,
the minor groove should be signifi cantly straighter at the bulge site than in standard
canonical form DNA, and therefore, a potentially good binding site for the rigid
dinuclear ruthenium complexes.
D
D - [{Ru(phen)
2
}
2
( m - dppm)]
4+
(dppm = 4,6 - bis(2 - pyridyl)pyrimidine; Figure
11.2c) was shown to bind at the A3-bulge site of the nonself-complementary dodeca-
nucleotide duplex d(GCATCG
AAA
GCTACG) • d(CGTAGCCGATGC) with high
affi nity (
K
= 3
10
5
M
− 1
) and selectivity.
102
Interestingly, the NMR results suggested
that at least one of the phen ligands is bound by partial intercalation. Upfi eld shifts
of similar magnitude were observed for the phen resonances in a study of the
binding of the well-known intercalating agent [Pt(en)(phen)]
2+
(en = ethylenedia -
mine) to a hexanucleotide.
103
While the minor groove is no wider at the A3-bulge site
compared to the normal duplex regions, molecular models showed that the smaller
helical twist coupled with the 50 ° bend towards the major groove results in the minor
groove being straighter at the A3-bulge sequence. This allows the bridging dppm
ligand to follow the groove, and hence, fi t more fully within the groove at the bulge
site. Furthermore, possible steric clashes with the oligonucleotide backbone are also
reduced for the two phenanthroline ligands that are almost parallel with the bridg-
ing dppm ligand. The remaining two phenanthroline ligands are then ideally placed
to be inserted deeply within the duplex structure, as shown in Figure 11.7.
×
11.3.4 Interaction of Dinuclear Complexes with DNA Hairpin Sequences
DNA hairpin sequences, or stem-loop structures - shown in Figure 11.8 - are sec-
ondary structural motifs known to arise naturally in base sequences possessing
self-complementarity. Although not as common as in RNA, DNA hairpins and cru-
ciforms (two opposed hairpins) are believed to play a role in a variety of fundamen-
tal biological processes, including the control of gene expression and mutagenic
events.
104 - 109
Many potential hairpin or cruciform structures have been identifi ed in
genomic DNA in regions associated with the regulation of transcription.
105,106
Addi-
tionally, a number of DNA-binding proteins have been found to preferentially
target such sequences.
110 - 113
Conversely, a number of neurological diseases have
been attributed to the disadvantageous formation of hairpin structures during the
replication of trinucleotide repeat sequences.
114,115
Hence, there is also signifi cant
interest in the design of small molecules that specifi cally target hairpin structures.
The complexes
meso -
[{Ru(phen)
2
}
2
( m - HAT)]
4+
and
meso -
[{Ru(4,7 - Me
2
phen)
2
}
2
(m - HAT)]
4+
(4,7 - Me
2
phen = 4,7 - dimethyl - 1,10 - phenanthroline; Figure 11.1 g) were
shown to bind an icosanucleotide that contains a seven-base-pair stem section and
a six-base loop region with greater affi nity than the corresponding four-base loop
octadecanucleotide and three control duplex dodecanucleotides.
116
Based on the
results from one- and two-dimensional NMR spectra, models of
meso -
[{Ru(phen)
2
}
2
(m - HAT)]
4+
and
meso -
[{Ru(4,7 - Me
2
phen)
2
}
2
( m - HAT)]
4+
bound to the six-base
hairpin were produced. Each complex bound on the minor-groove side of the
