602
Chirality in Biology
O
R
OH
H
O
O
HO
H
O
(a)
(b)
R
O
H
N
H
C
6
H
5
R
O
H
N
HO
H
R
O
R
N
H
O
2
3
(c)
(d)
(e)
Fig. 14
Chiral drugs.
(
a
)
=
(
S
)
-ibuprofen, R
=
CH
3
CH(CH
3
)CH
2
;
(
b
)
=
(
S
)
-warfarin;
(
c
)
=
(
R
)
-fluoxetine (trade name, Prozac),
R
=
CF
3
-C
6
H
4
;
(
d
)
=
(
S
)
-propranolol, R
=
C
10
H
7
;
(
e
)
=
(
2
R
,3
S
)-propoxyphene (as hydrochloride, trade name Darvon),
R
=
C
6
H
5
.
cardiac side effect at high dosage, and
development was discontinued.
Case 2. One enantiomer has the desired
physiological activity, the other does not.
For propranolol, a
β
-adrenergic blocking
agent, the (
S
)-(
)compound(F
ig
.14d
)is
much more effective than the enantiomer;
the activity ratio, S : R, is 100 : 1. However,
like many drugs, propranolol has other
activities. As a local anesthetic, as a regula-
tor of thyroxine metabolism, in membrane
stabilization, and for psychiatric use, the
enantiomers are equipotent. Propranolol
shows complex, enantioselective pharma-
cokinetic behavior. The (
S
) enantiomer
accumulates selectively in the heart with
the (
R
) enantiomer remaining largely in
blood and being stereoselectively metabo-
lized.
Case 3. The two drug enantiomers have
different pharmacological activities one of
which may be either desirable or not.
Both enantiomers of propoxyphene have
useful, different activities. The (2
S
,3
R
)-(
+
)
enantiomer is an analgesic (trade name
of hydrochloride, Darvon, Fig. 14e), while
the (2
R
,3
S
)-(
) enantiomer is marketed
as a naphthalene sulfonate (trade name,
Novrad) for use as an antitussive. Darvon
read in reverse is Novrad, but the two
names are not exact mirror images.
Thalidomide (trade name, Contergan)
is often considered as a Case 3 com-
pound but the actual situation is com-
plex.
Use
of
the
racemic mixture
as
a
sedative
and
antinausea
agent
by
pregnant women (although not in the
United States) beginning in about 1956
was
responsible
for
the
birth
of
the
so-called
thalidomide
babies
–worldwide
about 10 000 cases of phocomelia – before
it was withdrawn from the world mar-
ket. Early animal work suggested that
the teratogenic action was associated with
(
S
)-(
) thalidomide (Fig. 15a), which un-
derwent metabolism successively to
N
-
phthaloylglutamine (Fig. 15b, R
=
NH
2
)
and
N
-phthaloylglutamic acid (Fig. 15b,
R
=
OH). The latter compounds with L(
S
)
con±gurations were teratogenic and the
D(
R
) metabolites were harmless. How-
ever,
this
work
has
apparently
never
been con±rmed independently, and there
is a dif±culty. Thalidomide undergoes
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