Chemistry Reference
In-Depth Information
It was therefore challenging to determine if such Pt(II) complexes were able
to cross link the quadruplex structures of the human telomeric sequence, AG
3
(T
2
AG
3
)
3
.
Indeed, they contain only four adenines in the loops and stem that are accessible
to Pt(II) complexes (Figure 7.3). Moreover it was of pharmacological interest to
establish if such a crosslink might exist and have similar cellular effects to those of
compounds stabilizing the G-quadruplex structures.
96,131
The results of the
in vitro
platination of the human G-quadruplex structures by the monofunctional platinum
complex [Pt(II)(NH
3
)
3
(H
2
O)]
2+
was surprising because, in addition to the four
adenines, some guanines were platinated, whereas their N7 atom was expected to
be involved in hydrogen bonds into the G-quartets. Thanks to unconstrained molec-
ular dynamics simulations run on the antiparallel and on the parallel structures
(Figure 7.9), it was possible to rationalize the platination of these specifi c guanines.
Indeed, the simulations clearly showed that both structures were fl exible and that
the G-quartet located at the transversal loop side of the antiparallel structure could
be disrupted, allowing the N7 atoms of G2, G10, G14 and G22 to be platinated.
Moreover, two guanines located in the G-quartet of the 5
extremity of the parallel
structure were also shown to slip out of the G-quartet, rendering their N7 atoms
(G8 and G20) accessible to platination. Since the adenines of the loops and some
guanines of the G-quartets are potential platination sites, crosslinks of human telo-
meric G-quadruplex structures by difunctional Pt(II) complexes may be envisioned.
Actually, we showed that the antiparallel structure was crosslinked by the difunc-
tional Pt(II) complexes,
cis
- and
trans
- [Pt(II)(NH
3
)
2
(H
2
O)
2
]
2+
, between an adenine
and a guanine, (A1-G10, A13-G22), as well as the two adenines located at both
ends of the structure (A1-A13, A7-A19).
125
These results indicate that purines of the parallel structure (A-A or A-G) are
not close enough to be crosslinked by the mononuclear difunctional platinum
′
G20
G10
G2
G14
G8
G-quartets
G22
Anti-parallel structure Parallel structure
of the human telomeric DNA sequence AG
3
(T
2
AG
3
)
3
Figure 7.9
Conformation of the antiparallel and the parallel structures AG
3
(T
2
AG
3
)
3
from
molecular dynamics simulations. The top G-quartet of the anti-parallel structure can be com-
pletely disrupted whereas the top G-quartet of the parallel structure can lose two guanines.
The slipping out of these guanines render their N
7
atom accessible to platinum complexes.
(Adapted from
Biochemistry
, 2005,
44
, 10620-10634.)
