Chemistry Reference
In-Depth Information
much higher. Thalidomide caused birth deformities when tested (retrospec-
tively) in rabbits and in primates, as well as in humans, but tragically, the
initial toxicology screen for the drug had been carried out in rats. It is now
known that rats metabolise the drug differently from humans and, as a
result, birth defects were not detected in the animal testing. The structure
of thalidomide is shown in Figure 4.14 with the chiral centre indicated.
O
O
H
H
N
O
N
O
N
N
O
O
O
O
H
H
(
R
)-Thalidomide
(
S
)-Thalidomide
Figure 4.14
The enantiomers of thalidomide.
The drug was administered as the racemic mixture but, whereas the
(
R
) isomer was an effective sedative, the opposite (
S
) isomer was found to
have teratogenic properties and to cause deformities in the developing fetus.
The toxic effect of thalidomide is most profound on new blood vessels
developing in the fetus, a process called
angiogenesis
. The drug damages
these delicate structures, transport of essential nutrients to the growing
limbs is prevented, and the limbs do not develop properly. The period of
pregnancy when the symptoms of morning sickness are most severe coin-
cides almost exactly with the period of most rapid limb growth in the fetus,
so, unfortunately, the drug was taken at the worst possible time during the
pregnancy to damage the fetus. In cases of drug toxicity like this when one
enantiomer is active (often called the
eutomer
) and the opposite enantiomer
is toxic (called the
distomer
), the obvious solution is to resolve the racemic
mixture into the two enantiomers and administer only the safe (
R
) isomer
as a pure enantiomer. Unfortunately, it is now known that, in the case of
thalidomide, administration of the enantiomerically pure (
R
) isomer would
not have prevented the disaster since this isomer undergoes racemisation
in
vivo
; in other words, administration of the pure enantiomer results in
formation of a 50/50 racemic mixture in the bloodstream. The half-life for
this reaction has been determined as 566 minutes at 37
C and pH 7.4. This
means that even if pure (
R
) isomer had been given, in a little less than 10
hours half of it would have been converted into the toxic enantiomer.
The situation is (even) more complicated because thalidomide is
metabolised in the body and the metabolites themselves may be toxic. The
