Chemistry Reference
In-Depth Information
assumed to be DNA. Cisplatin becomes activated intracellularly by the aquation of
the two chloride leaving groups, leading to
cis
- [Pt(II)(NH
3
)
2
(H
2
O)
2
]
2+
, and subse-
quently covalently binds to DNA, mainly forming intrastrand crosslinks on DNA
between two adjacent guanines d(GpG) (65%) or adjacent adenine and guanine,
d(ApG) (25%), by coordinating to N7 of purine bases.
118 - 120
The antitumour effect
of cisplatin is attributed to the formation of the major GG adduct because the
tumour response correlates with the level of GG adducts. The recognition and
processing by DNA damage-response proteins
120
induce signal transduction path-
ways that lead to apoptosis or necrosis. However, although cellular responses to
platinum-induced damage have been widely studied
119, 121
all the biological targets
are not fully revealed. Since human telomeres consist of long tandem repeats of
TTAGGG sequences, they are potential targets for platinum complexes. Given that
telomeric nucleosomes are intrinsically more mobile under physiological conditions
than nucleosomes formed on an average DNA sequence,
94
one can envisage that
platination of telomeres could be kinetically favoured over average DNA. It is thus
conceivable that cisplatin may exert part of its anticancer activity via the formation
of DNA adducts at telomeres, altering the telomere structure and thus impeding its
access to telomerase, and/or lead to a loss of specifi c telomere binding proteins. It
is also possible that cisplatin could infl uence directly the telomerase activity by
binding to its RNA core, hTR. This review will present the advances in this fi eld.
7.6 Interaction of Cisplatin and Related Platinum Complexes with
G - Quadruplex Structures
Since metallo-organic complexes appeared recently as promising new G-quadruplex
binders,
97
square planar Pt(II) complexes with extended aromatic ligands have been
prepared. Indeed, they provide a p-surface that is compatible with the G-quartet
motif. Although some of them have been extensively studied as duplex DNA binders,
they have been less studied for their recognition of G-quadruplex DNA. Only a few
examples of platinum-organic G-quadruplex binders are known to date. They
belong to two different classes: (i) Pt(II) complexes without any labile ligand, unable
to undergo platination reaction on the G-quadruplexes and therefore considered as
reversible binders; (ii) mono-functional Pt(II) complexes containing one labile
ligand (Cl
−
) potentially able to covalently link G-quadruplexes and considered as
potential irreversible binders in addition to their stabilizing effect.
(i)
Bipyridine and phenanthroimidazole ethylenediamine platinum (II) complexes
(Figure 7.7A) have been shown to interact with a 12-mer intermolecular
quadruplex - forming sequence (T
4
G
4
T
4
)
4
with two platinum complexes per
quadruplex.
122
Binding constants are in the range 10
6
- 10
7
M
− 1
increasing with
the p-surface of the complexes. They induce signifi cant stabilization of the
intermolecular G-quadruplex structure and increased preference of two orders
of magnitude for quadruplex over duplex. This binding mode is consistent with
an end-stacking platinum complex located at each side of the quadruplex struc-
ture. Molecular modelling studies of the Pt(II) complexes with the quadruplex
