Chemistry Reference
In-Depth Information
mechanism of cisplatin toxicity, either by hijacking the proteins away from their natural binding sites or, alter-
natively, by protecting the cisplatin adducts from DNA repair mechanisms. A number of other proteins have been
found to bind to platinated DNA.
Well in excess of 3000 cisplatin analogues have been synthesised in the search for platinum anticancer drugs with
broader spectrum of action against different tumours, fewer side effects and activity against cisplatin-resistant
tumours. Attention has focused on compounds which only form monofunctional DNA adducts, on trans-platinum
complexes, polyplatinum compounds, and platinum (IV) analogues, and the search continues. Statistically, for one
new clinically active compound to be discovered, 10,000 new compounds need to be synthesised and screened, so
high-throughput methodologies are being developed and the search for new cisplatin analogues continues apace.
Other Metals as Anti cancer Drugs
Because of the severe side effects, the restricted tumour spectrum and the acquired or intrinsic resistance,
alternative metal-based anticancer drugs are being actively pursued. Ruthenium compounds containing Ru
II
or
Ru
III
are considered to be suitable candidates: two ruthenium(III) complexes have entered clinical trials, trans-
[RuCl
4
(DMSO)(Im)]ImH (NAMI-A, where Im
¼
imidazole) and trans-[RuCl
4
(Ind)
2
]IndH (KP1019, where
Ind
¼
indazole). This is the ruthenium complex, their structures are presented in
Figure 22.9
. There are two
FIGURE 22.9
(a) Structure of NAMI-A. (b) Structure of KP1019.
important differences between KP1019 and most of the Pt-based anticancer drugs; (ii) the Ru complexes have
octahedral geometry compared to the square-planar Pt(II) drugs and (ii) the Ru complexes can transfer electrons,
easily passing from the Ru(II) to Ru(III) form, whereas reduction of Pt(IV) to Pt(II) requires both a change in
coordination number and in interatomic bond distance. This may go some way towards explaining why the Ru-
based drugs are assumed to have a different mode of action. Another important difference in the mode of action of
KP1019 is that it is transported by the serum protein transferrin and its transport into the cell is via the transferrin-
cell pathway (see Chapter 7). Since we know that rapidly dividing cells, such as cancer cells, express increased
numbers of transferrin receptors, this will effectively target the drug to tumour cells. In addition, the selective
activation by reduction in the tumour might contribute to the low side effects observed in in vivo studies. These
features distinguish it from the established platinum anticancer drugs and suggest that types of cancer which are
resistant to Pt drugs might be treatable with this drug.
