Download L3 Theoretical Course No. 326 Faculty of Pharmacy University Of Al

TAMMAR H. Ali
L3 Theoretical
Course No. 326
Faculty of Pharmacy
University Of Al-Muthanna
Stereochemistry
In this chapter, the three-dimensional shapes of molecules will be introduced
and, in particular, the unusual geometry that arises around a carbon atom
with four different substituents attached to it – an asymmetric carbon atom.
The relationships between the different types of isomerism are shown in
Figure 1.
Figure 1
Steric Features of Drugs
It is very important to realise that when drugs or medicines are administered
to the body there is the opportunity for chiral interactions. This is because the
human body is composed of enzymes and receptors that are protein in nature.
2
These proteins are polymers of 20 or so naturally occurring amino acids. With
the exception of glycine, all of these amino acids are chiral (all are L-series
amino acids – see later) and it must be expected that a chiral drug will interact
with these chiral receptors differently from its enantiomer.
A simple, non-invasive example of chiral discrimination can be seen using the
smell of volatile compounds. (-)-Carvone is a natural product with the smell
of spearmint oil. (+)-Carvone, the enantiomer, has the odour of caraway seeds
(Figure 2). The fact that our noses can detect a different smell for the tiny
concentration of each enantiomer present proves that our sense of smell is
stereospecific. This is an example of a general rule, which is that the body is
chiral and body systems can discriminate between enantiomers of chiral
drugs.
Figure 2: the structure of (+) and (-) carvone.
Regardless of the ultimate mechanism by which the drug and the receptor
interact, the drug must approach the receptor and fit closely to its surface.
Steric factors determined by the stereochemistry of the receptor site surface
and that of the drug molecules are, therefore, of primary importance in
determining the nature and the efficiency of the drug-receptor interaction.
With the possible exception of the general anesthetics, such drugs must
possess a high structural specificity to initiate a response at a particular
receptor.
3
Some structural features contribute a high structural rigidity to the molecule.
For example, aromatic rings are planar, and the atoms attached directly to
these rings are held in the plane of the aromatic ring. Hence, the quaternary
nitrogen and carbamate oxygen attached directly to the benzene ring in the
cholinesterase inhibitor neostigmine are restricted to the plane of the ring, and
consequently, the spatial arrangement of at least these atoms is established.
The relative positions of atoms attached directly to multiple bonds are also
fixed. For the double bond, cis- and trans-isomers result. For example,
diethylstilbestrol exists in two fixed stereoisomeric forms: transdiethylstilbestrol is estrogenic, whereas the cis-isomer is only 7% as active.
In trans-diethylstilbestrol, resonance interactions and minimal steric
interference tend to hold the two aromatic rings and connecting ethylene
carbon atoms in the same plane.
Geometric isomers, such as the cis- and the trans-isomers, hold structural
features at different relative positions in space. These isomers also have
significantly different physical and chemical properties. Therefore, their
distributions in the biological medium are different, as are their capabilities
for interacting with a biological receptor in a structurally specific manner. The
United States Pharmacopeia recognizes that there are drugs with vinyl groups
whose commercial form contains both their E- and Z-isomers. Figure 3
provides four examples of these mixtures.
4
the anticancer drug tamoxifen is a notable example of a drug that is trans with
respect to the phenyl groups, but also (Z) when the Cahn–Ingold–Prelog
priorities are used (Figure 4).
More subtle differences exist for conformational isomers. Like geometric
isomers, these exist as different arrangements in space for the atoms or groups
in a single classic structure. Rotation about bonds allows interconversion of
conformational isomers. However, an energy barrier between isomers is often
high enough for their independent existence and reaction. Differences in
reactivity of functional groups or interaction with biological receptors may be
caused by differences in steric requirements of the receptors. In certain
semirigid ring systems, conformational isomers show significant differences
in biological activities. Methods for calculating these energy barriers are
described next.
Open chains of atoms, which form an important part of many drug molecules,
are not equally free to assume all possible conformations; some are sterically
preferred. Energy barriers to free rotation of the chains are present because of
interactions of non-bonded atoms. For example, the atoms tend to position
themselves in space so that they occupy staggered positions, with no two
atoms directly facing each other (eclipsed). Non-bonded interactions in
polymethylene chains tend to favor the most extended anti conformations,
although some of the partially extended gauche conformations also exist.
Intramolecular bonding between substituent groups can make what might first
appear to be an unfavorable conformation favorable.
Z-Clomiphene
5
Z-Cefprozil: R1= H; R2 = CH3 E-Cefprozil: R1 = CH3; R2 = H
Z-Doxepin: R1 = CH2CH2N(CH3)2; R2 = H E-Doxepin: R1 = H; R2 =
CH2CH2N(CH3)2
Figure 3 Examples of E- and Z-isomers.
6
Figure 4: The structure of tamoxifen.
The introduction of atoms other than carbon into a chain strongly influences
the conformation of the chain (Fig. 5). Because of resonance contributions of
forms in which a double bond occupies the central bonds of esters and amides,
a planar configuration is favored in which minimal steric interference of bulky
substituents occurs. Hence, an ester may exist mainly in the anti, rather than
the gauche, form. For the same reason, the amide linkage is essentially planar,
with the more bulky substituents occupying the anti-position. Therefore, ester
and amide linkages in a chain tend to hold bulky groups in a plane and to
separate them as far as possible. As components of the side chains of drugs,
ester and amide groups favor fully extended chains and also add polar
character to that segment of the chain.
7
Stabilized planar structure of amides
Figure 5 • Effect of noncarbon atoms on a molecule's configuration
In some cases, dipole-dipole interactions appear to influence structure in
solution. Methadone may exist partially in a cyclic form in solution because
of dipolar attractive forces between the basic nitrogen and carbonyl group or
because of hydrogen bonding between the hydrogen on the nitrogen and the
carbonyl oxygen (Fig. 6). In either conformation, methadone may resemble
the conformationally more rigid potent analgesics including morphine,
meperidine, and their analog, and it may be this form that interacts with the
analgesic receptor. Once the interaction between the drug and its receptor
begins, a flexible drug molecule may assume a different conformation than
that predicted from solution chemistry.
An intramolecular hydrogen bond usually formed between donor hydroxy and
amino groups and acceptor oxygen and nitrogen atoms, might be expected to
add stability to a particular conformation of a drug in solution. However, in
aqueous solution, donor and acceptor groups tend to be bonded to water, and
8
little gain in free energy would be achieved by the formation of an
intramolecular hydrogen bond, particularly if unfavorable steric factors
involving non-bonded interactions were introduced in the process. Therefore,
internal hydrogen bonds likely play only a secondary role to steric factors in
determining the conformational distribution of flexible drug molecules.
Figure 6 • Stabilization of conformations by secondary bonding
forces.
9