Chemistry Reference
In-Depth Information
NH
2
Me
O
OH
NH
2
(CH
2
)
6
Pt
N
NH
2
Me
O
NH
2
Me
N
O
activator
[O]
NH
3
aq HCl
pH 2,3
NH
2
OPO
TTTT
(CH
2
)
6
Pt
iPr
2
N
PO
OCNE
TTTT
Cl
O
NH
2
Me
protecting
group
= solid matrix
CNE = 2-cyanoethyl
[O] = oxidation (phosphite to phosphate)
Figure 9.9
Platinated oligothymidines with one labile bond are obtained by reacting the
phosphitylated, resin-linked oligothymidine and a masked platinum complex with an append-
ing hydroxyl group, followed by removal of the protecting groups
At the same time, the van Boom, Lippert and Reedijk groups developed a
parallel alternative to tether a platinum complex with one labile bond to oligonu-
cleotides.
54
Their strategy involved phosphitylation of the 5
- hydroxyl of a resin -
linked oligonucleotide chain, and the subsequent reaction of the resulting
phosphoramidite with a platinum complex that contained a hydroxyl group (Figure
9.9). After the oligothymidine deprotection step with aqueous ammonia, treatment
with aqueous HCl (pH = 2.3) removed the platinum protecting group and intro-
duced a labile chloride group, as required for crosslinking to a complementary
sequence. Further development of this approach, in particular optimization of the
platinum protecting group to render its elimination compatible with any oligonu-
cleotide sequence (in other words, with no risk of depurination), has not yet been
reported.
′
9.3.6 Regioselective Platination of Base - Modifi ed Oligonucleotides
Platinum(II) complexes can react with the nitrogen and sulfur nucleophiles of
amino acid side chains, as well as the heterocyclic nitrogen of nucleobases. Since the
formation of Pt-S bonds is the kinetically favoured reaction and many sulfur nucle-
ophiles are present in the cells, several research groups have studied the possible
transfer of platinum from sulfur to nitrogen and the competition between both
nucleophiles.
71 - 81
These studies showed the preference of platinum(II) complexes
for sulfur-containing species. Then, depending on the structures of the substrate and
the platinum(II) complex (stereochemistry, number of labile bonds), the initially
formed Pt-S adduct can evolve into monofunctional, bifunctional and even trifunc-
tional adducts in which Pt-S bonds are usually replaced by the thermodynamically
more stable Pt-N linkages.
The reaction between several peptide-oligonucleotide conjugates and
platinum(II) complexes such as cisplatin, Pt(dien) (dien=1,5 - diamino - 3 - aza -
pentane), Pt(en) and transplatin, revealed that some S-Pt-N adducts, in which
the metal linked methionine and either histidine or guanine, were quite stable. In
