Chemistry Reference
In-Depth Information
moiety is coordinated to a single purine, and in DNA/protein crosslinks in which
cisplatin coordinates a nucleobase and a protein molecule.
49,52 - 56
The structure of platinated DNA is signifi cantly distorted, resulting in a decrease
in melting temperature,
57
shortening,
58
unwinding
59
and local denaturation.
60
Results obtained in numerous cell lines suggest that cisplatin-damaged DNA
causes cell cycle perturbation and arrest in the G2-phase to allow for damage repair.
In the case of inadequate repair, the cell eventually undergoes an abortive attempt
at mitosis that results in cell death via an apoptotic mechanism.
56,61 - 64
Transplatin is not able to form 1,2-intrastrand crosslinks because of the
trans
disposition of the two coordination sites; instead it may form 1,3-intrastrand
crosslinks between two G residues separated by at least one base. The amount of
monofunctional adducts and protein-DNA crosslinks is much higher for transplatin
than for cisplatin. Another difference between the two isomers is that interstrand
crosslinks formed by transplatin are between complementary G and C residues,
whereas cisplatin forms only interstrand crosslinks between G residues. It was
reported that, under physiological conditions, transplatin forms mainly monofunc-
tional adducts, thus allowing the formation of protein-DNA crosslinks.
64
In vivo
,
transplatin interstrand crosslinks might not form because of the slow rate (
t
1/2
24 h)
of the crosslinking reaction and the trapping of the monoadduct species by thiol-
containing amino acids.
65,66
As stated earlier, DNA binding of platinum complexes is considered to be
responsible for their cytotoxic effect. DNA containing platinum adducts is structur-
ally distorted with respect to normal B-DNA, resulting in a loss of stability. The
structural aspects of platinated DNA have been thoroughly investigated using NMR
spectroscopy,
67 - 71
X - ray crystallography
72 - 74
and gel electrophoresis.
75
≈
5.1.3 Model Compounds
cis
- A
2
PtG
2
complexes, in which A
2
is a bidentate amine or two monodentate amines
and G is a guanine derivative bound to platinum via N7, are the most simple models
of the G/G crosslinks formed by cisplatin.
76 - 83
However, even these most simple
models can adopt conformations differing in the relative orientation of the two
guanine bases. The G bases can be in a head-to-head arrangement (HH), in which
both H8 atoms lie on the same side of the platinum coordination plane, or in a
head-to-tail arrangement (HT), in which the H8 atoms lie on opposite sides of the
coordination plane (LHT and D HT, Figure 5.4 ).
In the solid state, the large majority of
cis
- A
2
PtG
2
complexes adopt the confor-
mation with the six-membered rings of the two guanines on opposite sides of the
platinum coordination plane.
84 - 89
In only a few cases (all complexes contained 9-
ethylguanine except one that contained 9-(2-methoxy-ethoxy)guanine) was the HH
conformation found.
85,90,91
In solution,
cis
- A
2
PtG
2
complexes usually exhibit free rotation about the Pt-N7
bonds.
92 - 95
In a pioneering study, Cramer demonstrated that guanosine rotation can
be slowed suffi ciently to detect atropisomers on the NMR timescale, if A
2
is a suffi -
ciently bulky chelate (e.g. N,N,N
- tetramethylethylenediamine, Me
4
en).
92
Two G
′
,N
′
