Chemistry Reference
In-Depth Information
H-phosphonate chemistry was used throughout chain elongation. They found that
it was more diffi cult to incorporate the platinated synthon than the natural nucleo-
side H-phosphonates. Final deprotection with concentrated aqueous ammonia
afforded crude oligonucleotides showing rather complex HPLC profi les, and the
coordination sphere of the metal was modifi ed. Pyridine had replaced chloride,
yielding platinated oligonucleotides with no potential to react with the nucleophiles
of a complementary chain. Side reactions during fi nal deprotection and work-up
were held to account for the low quality of the crudes.
The same sequence of steps was described in Lippard's study,
65
but H-
phosphonate chemistry was only used to introduce the platinated monomer, while
standard phosphite triester chemistry was used for all the other nucleosides. The
authors indicated that after incorporation of the platinated unit the synthesis cycle
was modifi ed, but no details were given. Elongation of the full oligonucleotide chain
was followed by incubation in water to allow a 1,2-intrastrand G-Pt-G chelate to
form, and then by the cleavage and deprotection treatment. A fairly pure platinated
oligonucleotide, albeit in low yield, was obtained, but the authors indicated that the
protocol still required optimization.
All these results indicate that the introduction of platinated nucleoside building
blocks within the chain was neither straightforward nor easy to optimize. Although
labile substituents seemed to be compatible with oligonucleotide elongation using
phosphoramidites,
65
subsequent studies from other groups showed that they could
react with phosphoramidite derivatives.
60,66
The attempts of the groups of van Boom, Reedijk and Lippert to prepare pla-
tinated oligonucleotide analogues, in particular peptide nucleic acid chains (PNAs),
by solid-phase synthesis are also worth mentioning here.
67
The
N
- Fmoc -
N
2 - Bhoc
(Bhoc = benzhydryloxycarbonyl) guanine - containing PNA monomer was reacted
with a transplatin analogue to afford an
N
7 - platinated guanine building block
with a labile chloride ligand (Figure 9.6B). This monomer was then introduced at
the
N
-terminal of resin-linked, protected PNA chains. Then, following treatment
with trifl uoroacetic acid, which removes all protecting groups, target-platinated
PNAs were obtained. The key point for the success of the synthesis is that the fi nal
treatment is applied in conditions that do not block the reactive position at the
metal centre. This contrasts with the effect of the ammonia treatment used for the
fi nal deprotection of oligonucleotides, which provides an unreactive platinated
oligonucleotide.
9.3.4 Regioselective Platination of Partially Protected Oligonucleotides: Use of
O
6 - Guanine Protecting Groups
The van Boom and Reedijk groups explored an elegant alternative, in which
platinum is directed to the desired guanines while the reaction with other
guanines is prevented by the introduction of a bulky protecting group at the
O
6
position.
68,69
The preliminary study
68
found that
N
2-protected guanines could be platinated
at the
N
7 position, unlike
O
6,
N
2-protected ones that could not (Figure 9.7). It also
