Chirality in Biology
603
Fig. 15
Thalidomide
metabolism.
(
a
)
=
(
S
)
-(
)-
thalidomide;
(
b
)
=
N
-phthaloyl-L-
glutamine, R
=
NH
2
;
(
b
)
=
N
-phthaloyl-L-glutamic acid,
R
=
OH.
N
H
N
O
O
O
O
N
O
O
R
COOH
H
O
(a)
(b)
rather rapid racemization under physio-
logical conditions. In rabbits, for exam-
ple, thalidomide isolated from plasma
2 h after intravenous injection was com-
pletely racemized. It has actually been
stated, ‘‘that it is practically impossible
to demonstrate stereoselectivity in any
in vivo
biological effect of thalidomide’’
(but see below). With dynamic capillary
electrokinetic chromatography, the enan-
tiomerization barrier,
1
G
#
,wasfoundto
be 102
±
1kJmol
1
at pH 8.
Physiological
effects
of
intravenous
injection
(rather
than
per
os
)o
f
thalidomide
enantiomers
into
male
volunteers
have
been
investigated.
Although
the
enantiomers
have
low
solubility
(ca.
0.3 mg mL
1
)
in
5%
glucose (pH 4–5) solutions, preparations
were obtained for injections containing
0.2 mg mL
1
. [The racemate has lower
solubility – 0.07 mg mL
1
– and is a likely
racemic compound (each crystal contains
equal numbers of each enantiomer) rather
than
a
racemic
mixture
(any
crystal
contains only one enantiomeric form)].
The solutions formed less than 1% of
the opposite enantiomer on 9 days of
storage. The
results
conFrmed
earlier
observations that sedation and sleep were
related to blood concentrations of (
R
)-
but not (
S
)-thalidomide. Immunological
effects (see below) have been attributed
to the (
S
) enantiomer. These observations
appear
to
conFrm
the
earlier
work
assigning teratogenic activity to the (
S
)-(
)
enantiomer.
To a surprising extent, racemic thalido-
mide
(only
available
on
prescription)
has
made
a
comeback
because
of
immunomodulatory and antiangiogenic
properties. It has been used to treat severe
recurrent aphthous stomatitis in AIDS pa-
tients and to treat systemic manifestations
of erythrema nodosum leprosum in pa-
tients receiving recombinant interferon-
γ
treatment for lepromatous leprosy. More-
over, racemic thalidomide inhibits repli-
cation of human immunodeFciency virus
Type 1 and has a modest ability to inhibit
tumor necrosis factor-
α
, an immune sys-
tem modulator. Some structural analogs
of thalidomide are more effective than
thalidomide itself.
Several anesthetics are chiral; this is
the
case
for
the
inhalation
anesthet-
ics halothane, enflurane, and isoflurane,
all used as racemates. Some work on
isoflurane indicated enantiomer effects
on pond snail nerve channels, where
the (
S
) enantiomer (±ig. 16a) was twice
as active as the (
R
) form in triggering
an anesthetic-activated potassium current.
In mice and rats, inhalation experiments
with isoflurane enantiomers indicated a
greater effect of the (
S
) form, but there
were
also
contradictory
results.
It
is
likely that any enantiomer-selective effects
for volatile anesthetics will be relatively
weak.
More deFnitive results have been ob-
served with intravenous anesthetics. One
material, etomidate, is actually used as
the single (
R
)-(
+
) enantiomer (±ig. 16b).
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