Chemistry Reference
In-Depth Information
at physiological pH, the two major conformers were
anti
/
anti
HH1 R and
anti
/
anti
HH2 R (bottom model in Figure 5.13). For both conformers the sugar pucker was
N and S for the 5
- G, respectively.
101
When the sample was kept for 1 day at
pH 10, where N1 was not protonated, the LHT2 R conformer became
′
and 3
′
30% abun-
dant.
103
In contrast to the derivative with d(GpG), for (
R,S,S,R
) - bip - Pt(GpG) only
the HH1 R variant was observed at any pH, and only a small population of L HT2
R was observed at pH 10.
103
∼
5.6.1 Interligand Interactions Stabilizing Different Conformers in Adducts with
Tethered Guanines
Investigations of adducts of retro models with d(GpG) and GpG dinucleotides, not
only revealed the dynamic behaviour of these intrastrand crosslink models, with the
possibility for each guanine to undergo ca. 180 ° rotation about the Pt-N7 bond, but
also highlighted the role of 'weak' interactions, not unlike those discovered in the
investigations with untethered
cis
guanines. In particular, in the HH conformer, a
key interaction appeared to be the repulsion between the electron-rich O6 atoms
of the two guanines. Because of such repulsions, the six-membered ring of each
guanine is forced to move further away from the
cis
guanine and closer to the
cis
amine ( ' 6 - out ' relationship). If the
cis
amine has an N-H on the same side of the
platinum coordination plane as the O6 of the guanine, an H-bond could possibly be
formed.
101
Between HT conformers, the DHT1 L appears to be a major component in the
case of adducts with the (
S,R,R,S
)-bip ligand, which in theory can provide two N-Hs
for H-bond formation with the O6 of the two guanines (this can be seen in Figure
5.7, in which, however, the two guanines are not tethered).
106
The LHT2 R con-
former can also form two guanine O6/NH
cis
amine H-bonds in adducts of (
R,S,S,R
) -
bip (this can also be seen in Figure 5.7, although here the two guanines are not
tethered); however, at acidic pH the LHT2 R conformer is a minor form compared
to the HH1 R and HH2 R (the latter only for the d(GpG) adduct) conformers, thus
indicating that the LHT2 R conformer is intrinsically less stable. The LHT2 R con-
former concentration increases at high pH, and this could be attributed to O6
becoming a better hydrogen-bond acceptor when N1 is deprotonated.
103
5.6.2 Multiple Conformers in Cisplatin Adducts with Tethered Guanine Bases
The
cis
- (NH
3
)
2
Pt(GpG) complex is probably very dynamic, undergoing rapid rota-
tion about the Pt-N7 bonds. The H8 signals of
cis
- (NH
3
)
2
Pt(GpG) are relatively
sharp (
∼
10 and 4 Hz for 5
′
- G H8 and 3
′
- G H8, respectively) at 21 ° C but broader
(
20 and 5 Hz, respectively) at 5 ° C.
103
Therefore, exchange between conformer
classes or between variants within a conformer class must be moderately fast at
21 °C and slower at 5 °C. Comparison to spectral data for bip-Pt(GpG) indicates
that
cis
- (NH
3
)
2
Pt(GpG) exists as a mixture of variants from both the D HT1 and
HH1 conformer classes;
103
thus, the most likely explanation for the broadening is
exchange between conformer classes. Analysis of the NMR shifts and CD signal
∼
