Chemistry Reference
In-Depth Information
H
2
N
NH
2
NH
3
N
Pt
N
NH
3
N
HN
NH
Cl
NH
3
N
N
N
Pt
NH
2
H
2
N
NH
3
Cl
NH
3
N
O
N
O
N
O
= oligonucleotide (protected when anchored to resin)
= solid matrix
Figure 9.12
Introduction of a chelating group in oligonucleotides using a convertible nucle-
oside, and regioselective reaction of the polypyrimidine chain with cisplatin.
While studying the effect of platinated aminoalkyl arms on triplex formation,
Miller
et al.
reported the synthesis of platinated oligopyrimidines in which one
cytosine was replaced by
N
4
- (2 - aminoethyl)cytosine.
85
The oligonucleotides were
assembled on a solid support, and the incorporation of a 4-triazole-deoxyuridine
derivative in the middle of the chain allowed the introduction of the aminoethyl
function by treatment with ethylenediamine. After ammonia deprotection and
cleavage, the aminoethyl arm of the unprotected oligonucleotide was transformed
into a Pt(dien) or
cis
- chlorodiammineplatinum(II)
complex
by
reaction
with
[Pt(dien)Cl]Cl or cisplatin, respectively (Figure 9.12 ).
9.4 Use of Platinated Oligonucleotides for Duplex Crosslinking
9.4.1 Initial Experiments
In 1983, Vlasov
et al.
described for the fi rst time the use of platinum(II) compounds
for crosslinking DNA duplexes.
86
The fi rst step was the reaction of a binuclear
platinum(II) compound incorporating two labile functions with the
N
7 of an oligo-
nucleotide containing a single guanine. Then, hybridization promoted reaction with
the guanine at the 5
end of the complementary strand and gave the interstrand
crosslink (Figure 9.13). Regioselectivity in the platination of the second strand,
together with the fact that noncomplementary chains were not crosslinked, showed
that complementarity is a key point in these processes. As a result, the authors
envisaged the possibility of using platinated oligonucleotides for damaging certain
sequences of nucleic acids
in vivo
.
Given the great affi nity of phosphorothioate groups for platinum(II) com-
plexes,
87
a few years later Orgel
et al
. introduced a single phosphorothioate group
at the 5
′
-end of an antisense oligonucleotide to mediate crosslinking to longer DNA
strands that contained a complementary sequence,
88,89
or even to proteins.
90
In these
′
