Chemistry Reference
In-Depth Information
9.3.5 Attachment of Platinated Units to Protected Oligonucleotides
A different approach for the preparation of platinated oligonucleotides is the incor-
poration of the platinated unit to the growing oligonucleotide chain instead of using
a platinated nucleoside derivative. In 1999, Ren, Cai and Segal studied the reaction
of a [Pt(en)Cl
2
] analogue containing an appending hydroxyl group with either a
phosphitylating reagent or a phosphoramidite derivative of thymine in the presence
of tetrazole (or a tetrazole derivative).
66
In the two cases the hydroxyl group reacted
with the phosphorus(III) derivative (Figure 9.8A), but the evolution of the resulting
complex was different depending on whether the reaction yielded a phosphora-
midite or a phosphite triester. In the fi rst case, the nucleophilicity of phosphorus
prompted quick displacement of one of the chlorides linked to platinum, affording
a double chelate. This platinated phosphoramidite could not be activated by tetra-
zole. Therefore, it did not react with free hydroxyl groups in a nucleoside or in an
oligonucleotide chain. The phosphite triester also behaved as a nucleophile, but the
resulting complex was a mixture containing a double chelate and the target
[Pt(en)Cl
2
] - derivatized nucleotide.
The same group also described
70
the synthesis of platinum complexes with no
chelating amines, also containing hydroxyl groups to allow attachment to oligonu-
cleotides (Figure 9.8B). However, to the best of our knowledge this methodology
has not been explored so far.
NiPr
2
NH
NiPr
2
H
2
N
R-OH
A
NH
H
2
N
P
Pt
P
O
OCNE
CNEO
NiPr
2
Pt
tetrazole
Cl
P
O
tetrazole
lCl
C
CNEO
NiPr
2
H
2
N
NH
Cl
OH
Pt
lCl
C
tetrazole
OCNE
iPr
2
N
H
2
N
NH
P
O
T
O
P
O
T
O
P
O
T
O
O
Pt
O
CNEO
CNEO
NH
Pt
NH
2
Cl
lCl
C
O
DMT
O
DMT
O
DMT
Cl
B
CNE = 2-cyanoethyl
DMT = 4,4'-dimethoxytrityl
OH
(CH
2
)
n
NH
2
Cl
Pt
NH
2
(CH
2
)
n
OH
Cl
Figure 9.8
Intramolecular reaction of phosphorus(III) reagents [(2-cyanoethoxy)bis(diiso-
propylamino)]phosphine and 5
-O-DMT-thymidine] with
derivatized [Pt(en)Cl
2
] complexes (A). Structure of a cisplatin analogue with two appending
hydroxyl groups (B)
′
-phosphoramidite derivative of 3
′
