Chemistry Reference
In-Depth Information
Cl
NH
3
Pt
H
3
N
Cl
G N G
G N G
N = A, C, T
+ complementary chain,
hybridization
G N G
G N G
C N' C
C N' C
N': base complementary to N
H
3
N
,
=
Pt
= oligonucleotide
NH
3
Figure 9.15
Hybridization of an oligonucleotide with a 1,3-
trans
-Pt(NH
3
)
2
chelate to the
complementary strand induces a rearrangement that crosslinks the two chains
the CGNG sequence, see Section 9.3.1 and Figure 9.4C),
45,53
they became unstable
upon pairing with their complementary DNA or RNA strands. This interaction
promoted the rearrangement of the 1,3-intrastrand chelate into an interstrand
crosslink between the 5
-G of the initially platinated triplet and its complementary
C, resulting in the covalent linkage of both strands (Figure 9.15). Since isomerization
kinetics were independent of the nature and concentration of salts in the reaction
medium, it was suggested that the mechanism involved direct nucleophilic attack of
the cytosine complementary to the platinated 5
′
-G residue. The process was not
dramatically affected by the nature of the residue (A, C or T) lying between the
chelated guanines.
Since the discovery of this reaction, some authors have attempted to optimize
the isomerization process and make platinated oligonucleotides effi cient therapeu-
tic molecules for the control of gene expression.
91
The rate of the interstrand
crosslinking reaction varied, depending on the sequence facing the intrastrand
crosslink, and was too slow when the complementary oligoribonucleotide
sequences were 5
′
-
O
-
methyloligoribonucleotides and modifying the complementary sequence so that the
triplet facing the chelate was replaced by
5′
UA or
5′
CA doublets, the rearrangement
was achieved within a few minutes.
92
In an experiment with a 12/11-mer in which a
d(AT) doublet replaced the CTC triplet in a regular duplex, an interstrand G-
N
7 -
Pt - A -
N
1 crosslink was formed.
93
Although this methodology has given promising results in blocking translation
both
in vitro
and in cultured cells,
94,95
its application in therapy is problematic. Again,
sequence restriction requires a maximum of two guanines in the GNG triplet in the
oligonucleotide to be platinated.
The same strategy was used to crosslink an antisense oligo-2
′
- CN
′
C (N
′
= any nucleotide). However, by using platinated 2
′
′
-
O
-
methylribonucleotide to the human telomeric sequence (T
2
AG
3
)
n
.
96
