Chemistry Reference
In-Depth Information
Table 1:
Differences in the properties of enantiomers.
CH
2
CONH
2
H
2
NCOCH
2
HO
2
C
CO
2
H
NH
2
H
2
N
Asparagine
H
H
(
S
) Bitter taste
(
R
) Sweet taste
O
O
Carvone
(
S
) Caraway odor
(
R
) Spearmint odor
Limonene
(
R
) Orange odor
(
S
) Lemon odor
O
H
OH
OH
OH
Chloramphenicol
NHCOCHCl
2
NHCOCHCl
2
O
2
N
O
2
N
(
R,R
) Antibacterial
(
S,S
) Inactive
OH
COMe
OH
C
OMe
Warfarin
OO
OO
(
S
) 5-6 More potent
hypoprothrombinaemic agent than (
R
) [2]
(
R
) Less active
The Thalidomide Tragedy
The thalidomide tragedy of 1961 in Europe is a landmark in drug regulation. The sedative-hypnotic drug
thalidomide exhibited irreversible neurotoxicity and teratological (mutagenic) effects as a result of which babies
were born deformed. The drug was prescribed to pregnant women to counter morning sickness. Thalidomide is a
racemate - of a glutamic-acid derivative - and in 1984, in the foreword of a topic on X-ray crystallography [3], the
following statement appeared: “The thalidomide tragedy would probably never have occurred if, instead of using the
racemate, the (
R
)-isomer had been brought on to the market. In studies..... it was shown that after i.p. administration
only the (
S
)-(-)-enantiomer exerts an embryotoxic and teratogenic effect.
The (
R
)-(+)-enantiomer is devoid of any of those effects under the same experimental conditions”. This quote has
been widely used subsequently, and was even alluded to in the citation for the 2001 Nobel Prize in Chemistry, which
was awarded to Knowles, Noyori and Sharpless for the development of catalytic asymmetric synthesis, and has had
a great impact on the development of new drugs [4]. Regrettably, the proposal that the thalidomide tragedy could
have been avoided if the single enantiomer had been used is misleading, for two reasons:
1.
First, it is based on unreliable biological data: the studies purported to show that (
S
)-(-)-thalidomide,
was in the mouse - a species that is generally regarded as unresponsive - and involved very high
doses [5]. However, earlier work in the rabbit, the species that is most sensitive to thalidomide, clearly
showed the equal teratogenic potency of its enantiomers [6].
2.
Second, the chiral centre in thalidomide is unstable in protonated media and undergoes a rapid
configurational inversion [7]. So, the individual enantiomers of thalidomide are both inverted rapidly
to the racemic mixture, process that occurs faster
in vivo
than
in vitro
[8].
Therefore, even if there were differences in the toxicity of the enantiomers of thalidomide, their rapid racemization
in vivo
would blunt them so that they could not be exploited. This case shows the importance of considering data in
full and not leaping to conclusions, however tempting these may be [9].
