Chemistry Reference
In-Depth Information
Figure 10.4
Organotin-DNA adduct formation
binding modes to the Sn(IV) centre through
31
P NMR analysis, wherein the Sn(IV)
centre could be bound in a chelate or nonchelate manner to the phosphate oxygen.
80
In
119
Sn Mossbauer studies, Barbieri observed the interaction of solvated Sn(IV)
species (R
2
SnCl
2
(EtOH)
2
and R
3
SnCl(EtOH), R= Me, Et,
n
- Bu,
n
- Oct or Ph), in
which possible DNA adducts, R
2
Sn(DNA)
2
and R
3
Sn(DNA) were observed as gel
phases (DNA condensation).
81 - 83
Adduct formation was proposed to occur by neu-
tralization of the anionic phosphate groups by the cationic Sn centre, with proposed
octahedral and trigonal bipyramidal structures (Figure 10.4).
Interestingly, while the active species for cisplatin antitumour activity is
known to be the hydrolysis product, ([(NH
3
)
2
Pt(OH
2
)
2
]
2+
) analogous Sn species,
[Me
2
Sn(OH)(H
2
O)
n
]
+
, Me
2
Sn(OH)
2
and Me
3
Sn(OH)(H
2
O)
2
did not interact with
native DNA.
84
Such observations led the authors to propose structure-activity rela-
tionships, wherein the ability of organotin(IV) complexes to bind DNA depends on
the lipophilicity of the complex. Therefore, as lipophilicity increases for R
n
Sn(IV)
in the series: R = Me
n
-Oct, so the tendency of the complex to
form DNA - condensates increases.
82
When formation of DNA condensates does
occur, the interaction was proposed to occur through electrostatic interaction
between ethanol solvated species and oxygen atoms of the phosphodiester groups
present. Later theoretical and model studies on organotin(IV)-DNA interactions
further supported the conclusions that binding of such species occurs through elec-
trostatic interaction with phosphate O atoms.
85,86
Binding of organotin(IV) species to O donor ligands in nucleotides has exhib-
ited pH dependence in a number of studies. For example, coordination of hydrated
[Me
2
Sn(IV)]
2+
with a series of nucleotides under acidic conditions (pH
<
Et
<
Ph
<
n
- B u
<
4) resulted
in binding through phosphate oxygen atoms. At intermediate pH (4-9.5), no interac-
tion occurred, while under basic conditions, (pH
<
9.5) the hydroxyl groups of the
sugar functionality present on the nucleotide were also capable of coordination to
the Sn centre, in particular if a second deprotonated hydroxyl group was adjacent
to the fi rst, to form a chelate complex.
8
Similar observations were made in elegant
studies on the interaction of Et
2
SnCl
2
(phen) with 5
>
- dGMP, using [
trans
- en
2
Os(
n
-
H
2
)](CF
3
SO
3
)
2
as
1
H - NMR probe.
8,75
In all cases, the pH dependence of the Sn-DNA
interaction was observed.
The chemical and structural differences between organotin complexes and cis-
platin would suggest that very different modes of antitumour activity are exhibited
by each. The principle sites of interaction for organotin species would appear
′
