Chemistry Reference
In-Depth Information
N
N
N
N
N
N
Pt
Pt
Pt
∆HT
HH
ΛHT
Figure 5.4
D
HT, HH, and
HT conformers. The G base is represented by an arrow, the tip
indicating H8. The chiralities of the two HT conformers are defi ned according to the handed-
ness of two straight lines: one perpendicular to the coordination plane and passing through
the platinum atom and the second connecting the O6 atoms of the two Gs
Λ
H8 signals were detected. In an insightful analysis, it was shown that, when the
cis
-
A
2
Pt moiety has local
C
2
symmetry, the asymmetric sugar renders the two possible
HT atropisomers magnetically nonequivalent, each with one H8 signal. Two H8
signals are also expected for the nonequivalent Gs of the HH atropisomer. The
observation of only two of the four possible signals could be best explained by the
presence of only the two HT atropisomers, consistent with most crystallographic
results.
84 - 89,96 - 99
The bulky A
2
ligand(s) often lacked NH groups. Although N,N
-
dimethylethylenediamine (Me
2
en) complexes also formed HT atropisomers, the
broad guanosine H8 signals revealed a rotation rate that was moderately fast on
the NMR timescale.
94
In conclusion, there is an intrinsic diffi culty in investigating dynamic nucleos(t)ide
complexes. The structure in the solid state may be very different from that in solu-
tion because of crystal-packing interactions. In solution, because of fast interconver-
sion between possible conformers, only one set of signals, the average of those of
individual conformers, is observed.
′
5.1.4 Retro Modelling
The 'dynamic motion problem' led us to construct analogues of cisplatin with bulky
ligands designed to reduce the dynamic motion by destabilizing the transition
state for Pt-N7 rotation (Figure 5.5). An important feature of the design was to
minimize steric effects in the ground state equilibrium species to allow conformers
likely to be present in dynamic
cis
- A
2
PtG
2
adducts to exist in the new adducts also.
We introduced the term 'retro modeling'
76
to emphasize that the models we
employed
76 - 81,100 - 105
are more complicated than the relevant molecule, cisplatin. By
reducing rotation rates by a billion fold,
76,77
retro models have enabled us to under-
stand the adducts of the highly fl uxional cisplatin drug with DNA constituents.
105
Retro model results
76 - 78,80,81,100,101,103,104,106
have called into question two concepts that
for many years were widely accepted from studies on dynamic platinum complexes:
(i) untethered Gs adopt an HT conformation in preference to the HH conforma-
tion
107
and (ii) single-stranded d(GpG) crosslinks favour the HH form, which under-
goes slow rotation about the Pt-N7 bonds.
108 - 112
