Chemistry Reference
In-Depth Information
Zn
2+
titration of IX was carried out to check if the expected accumulation of
negative electrostatic potential in the interior of a long sequence
33,34
(compared to
shorter ones) would lead to a higher Zn
2+
affi nity for the internal GG step, compared
with that observed for VIII.
36
The results clearly showed that there is no enhanced
selectivity for the internal Zn
2+
binding for the long sequence.
[Pt(dien)]
+
Ions
Numerous publications have dealt with the binding pattern of cisplatin anticancer
drugs to DNA (see Chapters 5-9 in this topic). One of the fi rst studies on this topic
involved enzymatic digestion of platinated DNA using the well known anticancer
drug cisplatin (
cis
- [PtCl
2
(NH
3
)
2
]).
50
HPLC analysis of the cleavage products showed
that cisplatin forms chelates spanning G and/or A residues with the following per-
centages : Pt-GG (65%), Pt-AG (25%), Pt-GA (0%). Apparently, the rule of
sequence-selectivity proposed for labile metal ion complexes based on
1
H NMR and
photochemical cleavage studies does not apply to nonlabile platinum complexes.
However, the mechanism of chelate formation does not necessarily follow the
sequence-selectivity of the initial formation of monofunctional adducts. The fact that
the 5
′
-monoadducts are formed more rapidly and chelate more slowly than the 3
′
-
monoadducts might refl ect the inherently greater reactivity of the 5
′
- G compared
to the 3
-G. The common view is that the monoaqua species of cisplatin make the
initial attack on DNA bases, although recent results have lead Chottard and cowork-
ers to suggest that cisplatin may undergo double hydrolysis before reacting with
DNA.
51
In most reported studies on the kinetics of monofunctional platination reac-
tions of single- and double-stranded oligonucleotides, both NMR spectroscopic
and chromatographic methods have been used to determine kinetic parameters. The
reactions involving bifunctional platinum complexes have usually been carried out
with single-stranded oligonucleotides. In these reactions an initial monofunctional
adduct is formed, which subsequently ring-closes to form a bifunctional chelate. The
proposed selectivity rule is based on the intrinsic binding properties of duplex DNA.
Sadler and coworkers showed that in a reaction between
15
N - labelled [PtCl(dien)]
+
and a single-stranded 14-mer d(ATACA
TGGT
ACATA), little kinetic preference
for platination of either 5
′
G sites was observed, while the single-stranded 8-
mer d(ATACA
TGG
) showed a distinct preference for 5
′
G or 3
′
- G platination.
52
Chottard
and coworkers, using hairpin-forming oligomers as duplex models, concluded that
the selectivity for monofunctional attack by Pt
2+
on 5
′
G - residues is dependent
on the ligand in the
trans
position (e.g. Cl
−
, H
2
O, OH
−
, NH
3
).
51
In a later study they
proposed a model for sequence-selective binding of cisplatin to DNA duplexes,
involving a combination of molecular potentials and N7 accessibility.
53
In a study
on selectivity of adduct formation between
15
N - cisplatin and 14 - mer duplexes con-
taining central AGT and GAT residues, respectively, Hambley and coworkers con-
cluded that 'the purine base on the 3
′
and 3
′
side of the pair exerts substantially greater
infl uence on the rate of binding at the 5
′
′
-base than does the 5
′
-base on the rate of
- base ' .
54
However, monofunctional binding of cisplatin to the TGAT
binding at the 3
′
