Chemistry Reference
In-Depth Information
O
H
3
C
H
3
N
O
O
change of
leaving
groups
Pt
O
H
3
N
change of
oxidation state,
leaving groups and
spectator groups
O
O
H
3
N
Cl
carboplatin
H
2
N
Cl
Pt
Pt
H
3
N
Cl
H
3
N
Cl
H
2
N
O
O
O
O
O
cisplatin
change of
leaving and
spectator
groups
Pt
H
2
CH
3
O
satraplatin
oxaliplatin
Figure 9.3
Evolution of the first generation platinum drug cisplatin into later generation drugs.
first orally-administrable platinum drug - in this case a platinum(IV) complex. A mode
of action that involves reduction to Pt(II)
in vivo
has been proposed. This drug shows no
neurotoxicity or nephrotoxicity, with bone marrow supression the dose-limiting adverse
effect; it is under consideration for approval as a drug in prostrate cancer treatment.
Platinum complexes are currently the best-selling anticancer drugs in the world, with
billion-dollar annual sales. Nevertheless, the search for better platinum drugs goes on,
including development of some polynuclear complexes. Chemotherapy with platinum drugs
can be effective, but may have severe side effects because the drugs are toxic and cannot
discriminate sufficiently between normal and cancer cells. Development of new drugs
centred on the introduction of components that deliver the drugs specifically to cancer cells
will assist in specificity and reduction of side effects.
9.1.3
Other Metallodrugs
Although platinum drugs have a well-established place in the array of treatments used
for cancer sufferers, they are not the only coordination complexes that exhibit activity.
Another class of complexes under examination as anticancer drugs are those of titanium.
One titanium(IV) anticancer drug,
budotitane
([Ti(bzac)
2
(OEt)
2
], Figure 9.4) has qualified
for clinical trials, and a range of organometallic compounds such as titanocene dichloride
(Figure 9.4) have shown promise. Ruthenium complexes are also under investigation as
potential anticancer drugs.
A gold(I) complex
auranofin
has been developed for the treatment of rheumatoid arthritis.
This is a typical linear two-coordinate complex of gold(I), with 'soft' S and P donors to
match the 'soft' metal ion (Figure 9.4). The bulky ligands here promote compatibility in the
bio-environment, and activity is influenced by the substituents on the RS
−
and R
3
P ligands.
Gold complexes have also been examined for antimicrobial, antimalarial and anti HIV
(human immunodeficiency virus) activity. A copper(II) complex (Figure 9.4) is effective as
a competitive inhibitor of HIV-1.
Vanadium compounds, mainly square pyramidal complexes of the type
[O V(O R O)
2
], act as insulin mimetics with potential in diabetes control if toxicity
issues can be overcome; one is in use as an orally-administered agent in animals. A pen-
tagonal bipyramidal complex of manganese(II), [MnCl
2
(
N
5
)], where
N
5
is a pentaaza
macrocycle with four amine nitrogen donors and one pyridine nitrogen donor, acts as a
