Chemistry Reference
In-Depth Information
is located in the minor groove, and the six-membered rings of the two guanines are
on opposite sides of the platinum coordination plane (head-to-tail, HT, conforma-
tion, Figure 5.15). Solution NMR data have been interpreted by analogy with the
results of the X-ray investigations.
46,70,114,142,143
A detailed description of these adducts
appears in some excellent reviews.
144 - 146
However, even in the case of DS oligonu-
cleotides, which are, per se, somewhat rigidly structured, some dispute exists as to
the fi ne structure of more dynamic regions, and the contributions of the sugar-phos-
phate backbone and of interligand interactions in determining the overall stereo-
chemistry remain rather uncertain.
For instance, no two NMR studies on duplexes have led to the same proposed
structure
46,68,70,107,147
and the diverse proposed solution structures generally lack the
features found in the X-ray structure of a 16-mer bound to rat HMG1.
148
These
variations in structure may be caused by spectral complications arising from dynamic
motion centred at the crosslink. For instance, the dihedral angle between crosslinked
guanines has been found to span all values between 25° and 75°. However, in a
relatively recent study of a 9-mer duplex, an NMR-based structural model with
many of the elements of the X-ray structure of a 16-mer bound to rat HMG1 was
reported,
114
and this 9-mer has many spectral features common to duplexes with a
pyrimidine - G - G - pyrimidine sequence.
If, as appears to be the case, the structure of crosslinked double-stranded oli-
gonucleotides is far from being rigid, it is likely that the conformation is deeply
infl uenced by 'weak' interligand interactions, which are diffi cult to detect, but which
can result in a different biological activity. This appears to be the case for oxaliplatin,
[Pt(oxalato)(dach)] (dach = 1,2 - diaminocyclohexane), for which only the
R,R
enan-
tiomer ((
R,R
)-dach carrier ligand) has been approved for clinical use.
141,144
We also
investigated the mutagenic activity of several platinum compounds with chiral
diamines and found that the
S,S
enantiomer was always a far greater mutagenic
agent than the
R,R
form, particularly in the case of dach and dab adducts (dab = 2,3-
diaminobutane).
149
In an insightful analysis the distortion of double-stranded oligo-
nucleotides modifi ed at a single site by dach-Pt or dab-Pt residues of different
chiralities (either
R,R
or
S,S
) was monitored by chemical probes. It was found that
different diamine enantiomers induced different types of distortion and, as a con-
sequence of these structural differences, the affi nity of the platinated oligonucle-
otides for proteins (e.g. HMG proteins) was different, as well as their processing by
repair systems.
150,151
5.7 Conclusions and Perspectives
In general, adducts of cisplatin (and cisplatin analogues) with nucleotides and SS
and DS oligonucleotides are highly dynamic systems that are diffi cult to investigate
with conventional techniques. In most cases intermolecular interactions will affect
the solid-state conformation; solution data are generally interpreted on the basis of
a single model even when the system is likely to be a mixture of rapidly intercon-
verting forms. Retro models have proven to be particularly useful in unravelling the
