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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