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214 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 7-2.The
R
and S enantiomers of warfarin.
FIGURE 7-3.Mirror images of irbesartan.
FIGURE 7-4.Enalaprilat and its enantiomer.
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CH 7 - STEREOCHEMISTRY AND DRUG ACTION 215
previous examples, flipping this mirror image 180° clearly shows that the orientations of all chiral
centers are opposite to one another. As such, this mirror image cannot be superimposed on enalaprilat and is indeed its enantiomer.
This example serves to illustrate two key points:
1. First, regardless of the number of chiral centers present in a molecule, enantiomers must
possess the opposite stereochemistry at every chiral center.
2. Second, while enantiomers can be drawn as their mirror images, this generally is not the
norm. Most enantiomers are represented by simply changing the stereochemistry at each
chiral center. The mirror images were used in the above examples to visually illustrate that
the compounds either met or failed the required criteria.
Test-taking tip: If you are ever given a drug molecule and asked to draw its enantiomer, it is
much easier to simply alter the stereochemistry at each chiral center than to try to draw the mirror
image.
Chemical and Physical Properties
With one exception, the chemical and physical properties of enantiomers are identical. Therefore,
the R and S enantiomers of warfarin that were previously discussed have identical molecular weights,
IR and NMR spectral properties, log P values, water/lipid solubility balance, dissolution rates, pKa
values of the β-dicarbonyl group, and percent ionization at any given pH value. They differ solely in
the direction, but not the magnitude, in which they rotate plane polarized light. As such, they are
also known as optical isomers.
From a pharmacy perspective, the ability to rotate plane polarized light to the right or to the
left is irrelevant. It does not confer any specific chemical, pharmacological, or therapeutic advantage
to drug action; however, it does serve to distinguish one enantiomer from another. The enantiomer
that rotates plane polarized light clockwise, or to the right, is known as the (+) isomer, and the enantiomer that rotates plane polarized light counterclockwise, or to the left, is known as the (–) isomer.
Each enantiomer rotates plane polarized light to the same magnitude or extent. For example, if the
216 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
(+) isomer of a drug molecule rotates plane polarized light 15° to the right, the (–) isomer will rotate
the light 15° to the left. Some drug molecules are marketed as a single, pure enantiomer whereas
others are marketed as a racemic mixture: a 50:50 mixture of both enantiomers. Racemic mixtures
do not have any net effect on the rotation of plane polarized light because one half of the molecules
rotates the light in one direction and the other half rotates the light to the exact same extent in the
other direction.
Designations for Enantiomers and Chiral Centers
Four stereochemical designations can be used to describe enantiomers: (+)/(–), d/l, /, and R/S. The
(+)/(–) and d/l designations are similar in that they identify only the direction in which the enantiomer rotates plane polarized light. The d designation is an abbreviation for dextrorotatory and, similar to the (+) designation, indicates that the enantiomer rotates plane polarized light to the right, or
clockwise. The l designation is an abbreviation for levorotatory and, similar to the (–) designation,
indicates that the enantiomer rotates plane polarized light to the left, or counterclockwise. Of the
two designations, the (+)/(–) designations are highly preferred because the d/l designations can be
confused with the / designations described below.
Neither the (+)/(–) nor the d/l designations provide any information about the actual configu-
ration of a chiral center and by themselves do not provide enough information to discern which
structure is responsible for a specific optical rotation. Given only the optical activity and the structures shown below, it is not possible to determine which enantiomer is the most pharmacologically
active. The pharmacological activity can be determined only by studies looking at receptor interactions. As an example, let’s examine albuterol. In evaluating its structure, it contains one chiral
center and can exist as one of two isomers, designated below as enantiomer 1 and enantiomer 2. It
is known that the (–), or l, isomer of albuterol is primarily responsible for its beneficial bronchodilating effects whereas the (+), or d, isomer has little therapeutic activity and may even contribute to
undesirable bronchoconstriction. Without any additional information beyond (+)/(–) and d/l designations, it is not possible to determine if enantiomer 1 or enantiomer 2 represents the active, (–)
isomer of albuterol.
In contrast to the (+)/(–) and d/l designations, the / designations, as well as the R/S designa-
tions that follow, refer to the absolute configuration, or steric arrangement, of the atoms about a
given chiral carbon. The / designations trace back to the work of Hermann Emil Fischer in the late
19th century. Using the enantiomers of glyceraldehyde, Fischer assigned the designation to the
(+) enantiomer and the designation to the (–) enantiomer.
The structures shown above are drawn in what is known as a Fischer projection. Fischer used
this two-dimensional depiction to more simply represent the three-dimensional nature of the chiral
carbon atom. In a Fischer projection, the horizontal bonds are assumed to project toward the viewer
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whereas vertical bonds are assumed to project away from the viewer. The actual configurations of
both enantiomers are shown below.
There are two major disadvantages to using the / designations. First, to use these d esignations,
it is necessary to chemically convert or correlate the structure back to either - or -glyceraldehyde.
Situations can arise in which this conversion or correlation becomes ambiguous, resulting in two
different correlations and two opposite assignments. Second, if there is more than one chiral center
in a molecule, it is possible that one chiral center can be correlated back to -glyceraldehyde while
the other can be correlated back to the isomer. For the most part, the / designations are rarely
used outside of amino acids, sugars, and their analogs.
Similar to the fact that the (+)/(–) designations provided no information regarding the configuration of a chiral center, the / designations (as well as the R/S designations that follow) provide
no information regarding the direction of rotation of plane polarized light. In other words, there is
absolutely no direct relationship between a (+)/(–) designation and either a / or R/S designation.
To illustrate this key point, let us look at two amino acids. Shown below and on the left is a Fischer
projection for the general structure of all naturally occurring -amino acids. Please note that there is
no (+)/(–) designation assigned to the general structure. The structures of serine and alanine shown
below have the same configuration of atoms about the chiral carbon atom and are both designated
as . Interestingly, -serine rotates plane polarized light to the left whereas -alanine rotates it to the
right. Both biomolecules have the same configuration but differ in the direction in which they rotate
plane polarized light. There are three key concepts to remember here.
1.
The (+)/(–) and d/l designations only identify the direction in which the enantiomer rotates
plane polarized light.
2. The / and R/S designations refer to the absolute configuration, or steric arrangement, of
the atoms about a given chiral carbon.
3. A complete stereochemical designation requires both a (+)/(–) or d/l designation and a /
or R/S designation.
In 1966, Robert Cahn, Christopher Ingold, and Vladimir Prelog published an unambiguous procedure to describe individual chiral centers. The Cahn-Ingold-Prelog system (or CIP system) involves
the following general rules. First, the atoms or functional groups attached to the chiral center are
given priorities according to atomic number and various sequence rules. Second, the molecule is
rotated so that the group with the lowest priority is directed away from the viewer. Third, the established priorities are used to determine if the remaining three groups are oriented in a clockwise or a
counterclockwise manner, as shown in Figure 7-5. The R designation, which comes from the Latin
word for right, is assigned if the orientation is clockwise whereas the S designation, which comes
from the Latin word for left, is assigned if the orientation is counterclockwise.
218 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 7-5.Assignment of
R
and S designations.
The assignment of priorities follows three sequence rules. The rules themselves are somewhat
simple; however, based on the complexity of a drug molecule, multiple steps are sometimes required
to correctly designate a chiral center.
Sequence rule 1: Prioritize the four atoms attached to the chiral center in terms of their atomic
number. Although it is not necessary to memorize the periodic table, it is important to
know the relative atomic numbers and priorities of the atoms commonly found on drug
molecules. These are shown in Table 7-1. There are additional rules for chiral centers that
contain different isotopes of the same atom (e.g., hydrogen, deuterium, tritium); however,
this is extremely rare in drug molecules and is not discussed here.
TABLE 7-1.Relative Atomic Numbers and Priorities of Atoms
Commonly Found on Drug Molecules
Priority Atom Atomic Number
Highest
Lowest
I 53
Br 35
Cl 17
S 16
P 15
F 9
O 8
N 7
C 6
H 1
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Sequence rule 2: If the chiral center is attached to two or more atoms that are the same, then
sequence rule 1 is applied to the atoms that are the same. This continues until a difference is
found among these atoms. As an example, if a chiral center is attached to a chlorine atom,
a nitrogen atom, and two carbon atoms, then the chlorine atom would have the first priority, the nitrogen atom would have the second priority, and the two carbon atoms would
be tied for the third priority. Using sequence rule 2, these two “tied” carbon atoms would
be examined. If one of these carbon atoms was part of a methyl group and the other was
part of an alkyl chain, then the carbon that was part of the alkyl chain would have a higher
priority (attached to C,H,H) than the methyl group (attached to H,H,H).
Sequence rule 3: When a double or triple bond is encountered, then the atoms are duplicated
or triplicated, respectively, when looking at priority.
Using these sequence rules, let us first look at a hypothetical example. The compound shown
below has a chiral center that is attached to an oxygen atom, two carbon atoms, and a hydrogen
atom. According to sequence rule 1, oxygen has the highest priority and hydrogen has the lowest
priority. The carbon atoms are initially “tied,” so we need to invoke sequence rule 2. Carbon atom A
is part of an aromatic ring. As drawn, it has a double bond to one carbon atom and a single bond to
another carbon atom. Using sequence rule 3, the carbon atom involved in the double bond is duplicated, so carbon atom A is designated as being attached to three additional carbon atoms. Carbon
atom B is part of an isopropyl alkyl chain. It is attached to two carbon atoms and one hydrogen
atom. Carbon atom A (C,C,C) therefore has priority over carbon atom B (C,C,H). Thus, the overall
priority for this molecule is oxygen atom > carbon atom A > carbon atom B > hydrogen atom. Note
that the hydrogen atom is projected into the paper and thus located away from the viewer. Applying
the previously mentioned priorities, it is seen that the other three atoms are oriented in a counterclockwise manner; thus, the correct designation for this chiral center is S.
The R and S isomers of warfarin were previously shown in Figure 7-2. As a second example, let us
further examine the R isomer of warfarin by applying the above-mentioned sequence rules to verify
that this designation is correct.
Using sequence rule 1, it is seen that the chiral carbon in the above molecule is attached to a
hydrogen atom and three carbon atoms. The hydrogen atom thus has the lowest priority. Using
sequence rule 2, we now need to examine carbon atoms A to C. Carbon atom A is attached to two
carbon atoms, one by a single bond and one by a double bond. According to sequence rule 3, the
double bond counts twice, so carbon atom A is attached to three carbon atoms (C,C,C). Carbon
atom B is attached to two hydrogen atoms (not shown) and a carbon atom (C,H,H). Carbon atom
C is similar to carbon atom A because it is attached to one carbon atom by a single bond and to
another by a double bond (C,C,C). At this point, carbon atom B can be designated as having a lower
priority than either carbon atoms A or C. To resolve the priority between carbon atoms A and C,
we need to move to the next adjacent carbon atoms. These have been identified above as carbon
220 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
atoms A′ and C′. Carbon atom A′ is attached to two oxygen atoms, again one by a single bond and
the other by a double bond. Carbon atom C′ is attached to a carbon atom by a double bond and to
a hydrogen atom. Thus, carbon atom A′ (O,O,O) has priority over carbon atom C′ (C,C,H), and the
side chain emanating from carbon atom A has priority over that emanating from carbon atom C. The
final priority is carbon atom A > carbon atom C > carbon atom B > hydrogen. Similar to the previous
example, the hydrogen atom is projected into the paper and thus away from the viewer. Using the
established priority, it is seen that the other three atoms are oriented in a clockwise manner, thus
verifying that this is the R enantiomer of warfarin.
Summary of Key Points Regarding Stereochemical Designations
• For drug molecules, the R/S or / designations are much more important than the
(+)/(–) designations because the former provides information regarding the configuration or steric arrangements of atoms about a chiral center. For this reason, the (+)/(–)
designations are often omitted when a single pure enantiomer is discussed.
• The R/S and / designations provide absolutely no information regarding what direc-
tion an enantiomer will rotate plane polarized light. Similarly, the (+)/(–) designations
provide absolutely no information regarding the configuration of atoms about a chiral
center.
• A pure enantiomer, regardless of how many chiral centers it contains, only has one
(+)/(–) designation that designates the net rotation of plane polarized light.
• Sugars, amino acids, and their analogs still use the / system to designate a specific
chiral center. Regardless of how many chiral centers are present, a pure enantiomer
would have only one / designation. As an example, naturally occurring glucose molecules have four chiral centers but are designated as -glucose.
• The R/S designations unambiguously identify the stereochemical arrangement of
atoms about a chiral center. Each R/S designation is assigned individually to each chiral center; thus, if a drug molecule had three chiral centers, it would have three R/S
designations. If one enantiomer had an R,R,S designation, the other enantiomer would
have an S,S,R designation.
Pharmacological and Therapeutic Differences
Between Enantiomers
The above discussions focused on the stereochemical arrangement of atoms about a chiral center
and the proper designations for these chiral atoms. It has already been noted that enantiomers have
identical chemical and physical properties, with the exception of the direction of rotation of plane
polarized light, and that this rotation provides no therapeutic advantage or disadvantage. The subsequent discussion focuses on the most important aspect of enantiomers: their ability to bind and
interact with their three-dimensional biological targets. Specifically, due to the different stereochemical arrangement of atoms, enantiomers differ in their abilities to bind to protein receptors, DNA,
enzyme sites, transport proteins, and other biological targets.
From a pharmacological and/or therapeutic perspective, enantiomers can be divided into four
groups based on their potency and activity.
Group 1: These enantiomers have identical potency and pharmacological action; there is really
no significant pharmacological or therapeutic difference between the two enantiomers.
This situation is extremely rare.
Group 2: These enantiomers have similar activities but different potencies. This is very common
among drug molecules in which one enantiomer is primarily responsible for the pharmacological activity and the other enantiomer is less active. An example of this is seen with
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warfarin, a drug previously discussed in this chapter. The S enantiomer of warfarin is three
to five times more potent as an anticoagulant than is the R enantiomer.
Group 3: These enantiomers have different pharmacological properties. Th is is a common occur-
rence and can be further subdivided. First, some enantiomers produce different effects, but
the different effects work together for a beneficial response. An example of this is seen with
methacholine (Figure 7-6), an acetylcholine analog used for the diagnosis of bronchial airway hyper-reactivity. The S enantiomer is equipotent with acetylcholine, while the R enantiomer is 20-fold less active; however, the R enantiomer inhibits acetylcholinesterase and
prevents the rapid degradation of the S enantiomer. Second, in some situations, one enantiomer produces the desirable effect while the other contributes to adverse effects and
toxicity. Additionally, there are situations in which both enantiomers produce the desired
effect, but the adverse effect is due primarily to one enantiomer. An example of this latter situation is seen with disopyramide (Figure 7-6). While both enantiomers provide a
beneficial antiarrhythmic effect, the S enantiomer is responsible for QT wave prolongation
and most anticholinergic adverse effects. Finally, one enantiomer may partially counteract
the beneficial effects of the other. An example of this is seen with albuterol (Figure 7-6). As
previously mentioned, the (–) isomer (which is the R enantiomer) of albuterol is responsible
for the beneficial bronchodilation effects, while the (+) isomer (which is the S enantiomer)
enhances bronchoconstriction and opposes the beneficial effects of the R enantiomer. For
this reason, albuterol is available as its pure R enantiomer.
FIGURE 7-6.Examples of enantiomers that have different pharmacological properties.
Group 4: In this group, essentially all of the activity resides in only one enantiomer and the
other is simply an inert compound. Similar to group 1, this is uncommon; however, it is
seen in some drug classes. Within the α-methyl acetic acid subclass of nonsteroidal antiinflammatory drugs (NSAIDs), the anti-inflammatory activity resides solely in the S enantiomer. Drugs within this subclass include ibuprofen, naproxen, flurbiprofen, and ketoprofen.
222 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Similar to diclofenac and fenoprofen (discussed in Chapter 2), these NSAIDs nonselectively
inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes.
The differences in potency and activity seen with the above examples are directly related to the
relative abilities of the enantiomers to bind to their biological targets. The enantiomer that is able
to form more interactions with its biological target is predicted to have enhanced activity compared
with the enantiomer that is not able to form all of these interactions. A good example of this concept is seen in the work of Leslie Easson and Edgar Stedman. The R-(–) enantiomer of epinephrine
was known to have a higher affinity for adrenergic receptors than the S-(+) enantiomer. In 1933,
Easson and Stedman put forth a simple hypothesis that states that the differences in the activity
of these two stereoisomers are due to differences in their receptor binding. As shown in Figure 7-7,
FIGURE 7-7.A comparison of the binding of
N
-methyldopamine to the adrenergic receptor.
R
-(–)-epinephrine, S-(+)-epinephrine, and
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R-(–)-epinephrine is able to make three key binding interactions with the adrenergic receptor. The
positively charged amine can form an ionic bond, the β-hydroxyl group can form hydrogen bonds,
and the catechol ring can form several interactions based on the aromatic hydroxyl groups and the
aromatic ring. In contrast, S-(+)-epinephrine can only form two key binding interactions with the
adrenergic receptor. Due to the stereochemistry of the chiral center, the β-hydroxyl group is oriented away from the required binding region and does not participate in the drug-receptor binding
interaction. As such, the S enantiomer can still interact with the receptor but provides less than
10% of the activity of the R enantiomer. To ensure that this loss of activity was due to this missing
binding interaction, Easson and Stedman also examined N-methyldopamine (i.e., the desoxy analog
of epinephrine). This desoxy analog has the same two binding interactions as S-(+)-epinephrine but
lacks the binding interaction of a β-hydroxyl group. It was found to have an activity similar to that
of S-(+)-epinephrine, thus supporting the hypothesis. The key point in this example is that the chiral
center of the most active enantiomer orients the functional groups in such a manner that the maximum
number of binding interactions can be achieved.
Steric hindrance can also play a key role in the activity of enantiomers. Any given biological
target has a finite amount of space that is available for drugs to bind. Some portions of a biological
target may tolerate only small groups while other portions may be able to accommodate larger
groups. The orientation of small and large functional groups at a chiral center may dictate which has
the better fit. The α-methyl acetic acid subclass of NSAIDs provides a good example of this concept.
As discussed above, the activity of this subclass of drugs resides solely in the S enantiomer. The
inability of the R enantiomer to produce an anti-inflammatory effect is due to its inability to sterically fit into the enzyme binding pocket of cyclooxygenase enzymes. As shown in Figure 7-8, both
S-flurbiprofen and diclofenac are active NSAIDs whereas R-flurbiprofen and the dimethyl analog of
flurbiprofen are inactive. Because diclofenac lacks an α-methyl group but still retains anti-inflammatory activity, the differences in the activity of the enantiomers of flurbiprofen cannot be explained
FIGURE 7-8.Structures and activities of `-methyl acetic acids, a subclass of NSAIDs.
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