Chapter 14 Inorganic Chemistry
CISPLATIN Metal ions, even many that are not essential
to biological function, can be used for
treatment of diseases. For example, complex
es of gold are used to treat rheumatoid
arthritis, and lithium is used to treat mani
c depression. The square planar complex
cis
[Pt(NH
) 32
Cl] (also known as 2
cisplatin
) is an antitumor drug used to treat ovarian,
testicular, and brain cancers. Its mode of
action highlights the importance of geometric
isomers in determining the properties of a complex and its reactivity toward
ligand
substitution
.
The structures of
cis
-[Pt(NH
) 32
Cl] and 2
trans
-[Pt(NH
) 32
Cl] are shown in Figure 14.8. 2
Although these two isomers differ only in th
e arrangement of the ligands around the
platinum, they differ greatly in their ability
to stop tumor growth. A look at the operation
of cisplatin suggests the reason. Chloride ion is a weak Lewis base and is readily displaced from metal complexes. Even water is a stronge
r base than chloride ion. Thus, dissolving
cis
-[Pt(NH
) 32
Cl] in water results in the stepwise r 2
eactions shown in Figure 14.12. Notice
that the chloride ligands are replaced by wate
r, but the ammonia is a stronger base than
water, so the ammonia molecules remain bonded to the platinum. This reaction is typical of a
ligand substitution reaction
, where one ligand is replaced by another. In a biological
setting, functional grou
ps on proteins and on DNA can act as ligands as well. Indeed, it is
the bonding between the platinum in cisplatin
and the lone pairs on two of the nitrogen
atoms on a DNA strand of the cancer cell that is
the main source of the antitumor activity.
The reactions represented in Figure 14.12
are written as dynamic equilibria. When the
drug is administered into the blood stream, it
is in an environment of relatively high
chloride concentration (~ 0.1 M). Le Châtelie
r’s principle tells us that a high chloride
concentration will shift the equilibrium to the left, so most of the drug remains in its original state. However, inside the cell nucleus
, the chloride concentration is much smaller
(~ 0.003 M). Consequently, the equilibrium s
hown in Figure 14.12 shifts to the right. The
resulting complex, in which both chlorides have
been replaced with two water molecules,
can then bind to the DNA, as depicted in
Figure 14.13. Once bound, the DNA ligand is
relatively unreactive.
The effect that the binding of platinum has on the shape of the DNA double helix is
dramatic. The DNA double helix bends 30-40o at the site of binding. The bend is
represented by
in Figure 14.13. Many cellular eventsα
are initiated with a reaction where
a protein ‘reads’ a specific sequence on the
DNA strand. This process is based almost
entirely on the ability of the protein to conform to the shape of the double helix.
H^3
NCHCCH2O
O
CH2
C OOH^3
NCHCCHO
O CH3CH3GlutamateValineFigure 14.11 Amino acids involved in sickle-cell anemia Two glutamates are replaced by two valines in people with sickle-cell anemia.HN^3Pt
HNCl^3ClOH HHN^3Pt
HNCl^3OH2++ ClHN^3Pt
HNCl^3OH2OH HHN^3Pt
HNOH^32
OH2+ Cl+1+1-1+2+1-^
Figure 14.12 Replacement of chloride with water© byNorthCarolinaStateUniversity