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complexes. In order to try to crosslink the parallel structure, we used the dinuclear
difunctional platinum complexes, [{trans-PtCl(NH
3
)
2
}
2
H
2
N(CH
2
)
n
NH
2
]Cl
2
(
n
= 2 or
6), in which two platinum coordination units are linked by a fl exible diamine linker
that allows long range crosslinks on duplex DNA.
132
We found that the parallel
structure was mainly crosslinked between two guanines at the 5
- end G - quartet
(G8-G10) and (G2-G20), respectively, and that the antiparallel structure was
crosslinked between two guanines at the 5
′
′
- end G - quartet (G2 - G10), (G10 - G22)
and (G2 - G14).
78
All these results highlight that human G-quadruplex structures may serve as
favourable platination targets, since some of their guanines can reversibly leave the
G-quartet plane, thus rendering their N7 atom accessible to platinum complexes.
Moreover, we have showed that platination of human telomeric G-quadruplexes by
cisplatin was kinetically favoured
in vitro
by a factor of about two over a duplex
containing a unique GG platination site.
126
Based on these results we have designed new platinum complexes combin-
ing a G - quadruplex binder
133
with Pt(II) in order to target more specifi cally G-
quadruplex structures. Firstly, a platinum-quinacridine complex (Pt-MPQ) has been
specifi cally designed to bind covalently in order to stabilize G-quadruplex struc-
tures.
127
The platinum moiety can reach the opposite external G-quartet and bind
to an accessible purine (Figure 7.10). Actually, this novel platinum hybrid complex
is shown to trap preferentially the antiparallel quadruplex structure by linking to
the guanines of the 5
-end G-quartet and also enhance quadruplex versus duplex-
DNA selectivity. More importantly, Pt-MPQ displays cytotoxic activities analogous
to that of cisplatin on various cell lines.
Another monofunctional hybrid platinum complex, a Pt(II)-acridine derivative,
Pt-ACRAMTU, (Figure 7.10) has also been synthesized. Initially, it was known to
form adenine adducts in duplex DNA. Later, it has been shown to bind preferen-
tially to the adenines of the TTA loops of the G-quadruplex of human telomeric
sequences and to react signifi cantly faster with G-quadruplex than with duplex
DNA.
134
It was proposed that the acridine was stacked on one of the external
G-quartets, which will favour the platination of an adenine of the neighbouring
TTA loops. Interestingly, the two hybrid platinum complexes (Pt-MPQ and
Pt-ACRAMTU) show major differences in their binding mechanisms to G-
quadruplexes. It is conceivable that the length of the linker between the platinum
moiety and the G-quadruplex binder governs the site of platination. However, the
reversible stacking reaction is quicker than the irreversible platination reaction in
both cases, suggesting that it is the binding reaction that will govern the platination
site. For Pt-ACRAMTU, the binding of the acridine and the platination reaction
will occur at the same side of the G-quadruplex. In this case, the guanines of the
G-quartet are protected from platination due to the p - stacking interaction with the
acridine. Thus, only N7 and N1 atoms of adenines in the loops are free and suscep-
tible to interact with Pt(II). For Pt-MPQ, the quinacridine moiety binds at one side
of the G-quadruplex and platination can occur at the opposite external G-quartet,
thanks to the linker. Since the guanines of the 5
′
- end G - quartet of the antiparallel
structure have been platinated by Pt-MPQ, it suggests that the quinacridine moiety
binds at the opposite 3
′
′
-end G-quartet. Moreover, it should be noted that no adenine
