Cephalexin

defined in terms of the D/L system. Thus, the British Pharmacopoeia (1993) defines ampicillin as (6R)-6-(a-D-phenylgrycylamino) penicillanic acid (4.35) and cephalexin as 7-a-D-phenylglycylamino-3-methyl-3-cephem-4-carboxylic acid (4.36). The side chain chiral centre being denoted by the D/L system and only in the case of ampicillin is the stereochemistry of the ring system indicated and then for only one of the three chiral centres. Within the literature the two possible diastereoisomers arising from the introduction of the side chain of such compounds are frequently referred to in terms of D and L.

It is important to appreciate that the stereochemical designations, R and S, are defined by a set of arbitary rules and that with respect to biological activity the relevant feature is the three dimensional spatial arrangement of the functionalities within the molecule. A change in one functional group may result in an alteration of the configurational designation but have no influence on the relative orientation of the functionalities required for biological activity with respect to one another. For example the active enantiomers of the 2-arylpropionic acid NSAIDs have the S-configuration (4.20) which corresponds to the R-configuration of the 2-aryloxypropionic acid herbicides (4.37). Similarly in the case of the P-blockers the active agents of the arylethanolamine series have the ^-configuration (4.38) whereas those of aryloxypropanolamine series have the S-configurational (4.39) designation.

The metabolism of a drug may also result in an alteration of configurational designation with no change in the spatial arrangement of the functionalities. For example fonofos (4.40*), a cholinesterase inhibitor, undergoes oxidation to yield fonofos-oxon (4.41) which is also active. As a result of the sequence rule designations the R-enantiomer of fonofos yields the S-enantiomer of fonofos-oxon and (5^-fonofos yields R)-fonofosoxon. In the case of fonofos this change in designation is important as the activity and toxicity of the R-enantiomer is greater than that of the S-isomer, whereas the situation is reversed for fonofos-oxon, i.e. S>R. Without an appreciation of the structures of the individual enantiomers it would appear that the activity of the oxygen derivatives showed the reverse stereoselectivity to the sulphur series which is obviously not the case.

4.2.2 The nomenclature problem in generic names

A major problem in therapeutics is the lack of readily available information on the stereochemical identity or composition of a chiral drug in standard reference works. In the majority of cases it is impossible to determine if the material being used is a single enantiomer, a racemic mixture, a mixture of diastereoisomers or some other possibility. It is frequently the case that the (±)-prefix is used to indicate that the material is a racemic

* The designation applied to structure (4.40) may appear to be incorrect, but in the Sequence Rule the participation of d-orbitals in bonding is neglected for assignment of designation, e.g. the bonds of sulphur atoms in sulphoxides are regarded as single.

mixture, but if the compound in question contains two chiral centres in its structure then four stereoisomeric forms are possible, i.e. two pairs of enantiomers and hence two racemic mixtures. Which of the two possible racemates is the drug or is it a mixture of all four stereoisomers? The use of the (±)-prefix in this case does not specify the composition of the material. There is therefore a need within drug nomenclature to provide a system of generic names which will indicate if a compound may exist in more than one stereoisomeric form and also the nature of the material used, i.e. single isomer or mixture. An examination of the current British National Formulary (No. 31, 1996) indicates a number of agents listed under the headings Lev or Levo, Dex or Dextro, e.g. levamisole, levodopa, levomepromazine, dexamethasone, dexamphetamine, dexfenfluramine, dextromethorphan, indicating that the material is a single stereoisomer. However, for the remaining agents there are no indications of the stereochemical nature of the material. The extention of the above approach to nomenclature to include prefixes such as rac, for racemic mixtures, diam, for mixtures of diastereoisomers and mep, for mixtures of epimers has been proposed.

4.2.3 Prochirality

Atoms which are bonded to two identical groups and to two other different groups are said to be prochiral. For example if either of the two methylene group hydrogen atoms in ethanol (4.42) were replaced by another group, e.g. deuterium, then the carbon atom (C1) becomes chiral and two enantiomeric forms are possible (4.43). If ethanol (4.42) is viewed from the side opposite the hydrogen atom indicated ** then the sequence of groups about C1 i.e. HO, CH3, H, is anticlockwise. If the molecule is viewed from the side opposite the hydrogen indicated * then the sequence of groups is reversed, i.e. clockwise. In terms of their molecular environments these two hydrogen atoms are not equivalent, the carbon atom C1 is prochiral and the two hydrogen atoms are said to be enantiotopic. If H** is arbitrarily preferred over H* then an R-designation is obtained and H** is designated pro-R and H* as pro-5 (4.44). Differentiation of enantiotopic groups may be of considerable significance in biochemistry and metabolism (see Section 4.3).

4.3 BIOLOGICAL ACTIVITY

That enantiomers can exhibit different biological activities has been appreciated for over a century. One of the first reported observations of the differential physiological actions

of stereoisomers was that of Piutti, who in 1886 isolated the enantiomers of the amino acid asparagine (4.45) and reported that the (+)-enantiomer tasted sweet and the (-)-enantiomer was bland. Similar observations have been reported for other amino acids and the enantiomers of the D-series taste sweet, whereas those of the L-series are either tasteless or bitter. Enantiomers may also exhibit different odours the (-)-enantiomer of carvone (4.46) smells of spearmint whereas (+)-carvone has an odour of caraway. The (+)-enantiomer of the related terpene limonene (4.47) smells of orange and the (-)-enantiomer of lemon.

The differential pharmacological activity of drug enantiomers was shown in the early years of the present century when the English pharmacologist Cushny demonstrated that (-)-hyoscyamine was more potent than the (+)-enantiomer and that (-)-adrenaline had much greater activity than its (+)-antipode. In order to rationalise the observed differences in pharmacological activity between enantiomers Easson and Stedman, in 1933, suggested a three point fit model between the more active enantiomer and its receptor. The enantiomer on the left (4.48) is involved with three simultaneous bonding interactions with complementary sites on the receptor surface. Whereas that on the right (4.49) may only take part in two such interactions. Alternative orientations of the enantiomer on the right (4.49) to the receptor site are possible but only two interactions may take place at any one time. According to the Easson-Stedman model the more potent enantiomer is involved with a minimum of three intermolecular interactions with the receptor surface whereas the less potent isomer may interact at two sites only. Thus the "fit" of the enantiomers to the receptor are different as are their binding energies.

The Easson-Stedman model is supported by data derived from an examination of the activity of (-)-R)-adrenaline (4.31). The three points of attachment of (R)-adrenaline being the secondary amino group, the catechol ring system and the alcohol hydroxyl group. Comparison of the activity of (R)- and (S)-adrenaline and that of the achiral desoxy compound N-methyldopamine indicates that the activity of the S-enantiomer and the achiral compound are the same. In the case of (S)-adrenaline the hydroxy group is orientated in an unfavourable position for three simultaneous interactions with the receptor and only a two point interaction is possible. Similarly, N-methyldopamine may also interact at two points, with the result that the activity is similar to that of (S)-adrenaline and much less than that of the R-enantiomer. Similar data has been obtained for the corresponding enantiomers and achiral derivatives of (R)-noradrenaline (4.30) and (R)-isoprenaline for both a and p adrenoreceptor activity.

In 1948 Ogston, unaware of the Easson-Stedman hypothesis, proposed a similar three point attachment model in order to rationalise the results from enzymatic studies using prochiral substrates. In the case of a compound CABBD (4.50) the two B groups are

enantiotopic and may be differentiated on interaction with an enzyme active site such that only one of the groups undergoes transformation. Ogston proposed that the substrate interacts with three sites on the enzyme but that only one of the complimentary sites to the enantiotopic groups B is involved with the biochemical transformation. If reaction can only occur at site B" then group B* in the substrate, but not group B, is converted in the product, i.e. the groups B and B* are not sterically equivalent.

Transformations of this type are relatively common in biochemistry and in drug metabolism. For example the synthesis of (-)-(^-noradrenaline (4.30) from dopamine (4.51), mediated by dopamine-P-hydroxylase, proceeds with total stereoselectivity, i.e. is stereospecific.

Similar specificity is shown by this enzyme in the metabolism of other substrates, e.g. (+)-S)-a-methyldopamine (4.52) to (-)-(1R,2S)-a-methylnoradrenaline (4.53). The antihypertensive agent a-methyldopa (4.54) is marketed as the single L-enantiomer corresponding to the S-configuration using the sequence rule designation. This agent undergoes decarboxylation, mediated by dopa decarboxylase, to yield (+)-(S)-a-methyldopamine (4.52), which then undergoes, dopamine ß-hydroxylase mediated oxidation to (1^,2S)-a-methylnoradrenaline (4.53), the active agent. As (+)-(S)-a-methyldopamine, is chiral the two hydrogen atoms on the ß-carbon atom are said to be diastereotopic rather than enantiotopic.

The above models are very useful but relatively simplistic representations of what may in fact occur during the drug, or substrate, interaction with a receptor, or enzyme,

and assumes that the drug has to adopt a particular orientation in relation to the receptor site. It is possible that the less active, or potent, enantiomer may also be involved in three intermolecular interactions with the receptor resulting from additional interactions with the biomolecule which do not occur with the more active enantiomer. It is also feasible to propose that the interactions do not necessarily need to be attractive, e.g. the interactions could be both attractive and repulsive. In addition the interaction between the drug and the receptor/enzyme target may result in conformational changes in both the target macromolecule and the ligand. Thus, the final interaction model may be fairly complex and both the stereochemistry and conformational flexibility of the ligand need to be taken into account.

4.3.1 Terminology used in the pharmacological evaluation of stereoisomers

The differential biological activity of a pair of stereoisomers has given rise to additional terminology. Thus, the stereoisomer with the higher receptor affinity, or activity, is termed the Eutomer and that with the lower affinity, or activity, the Distomer. The ratio of affinities, or activities, of the two stereoisomers, a measure of the stereoselectivity is known as the Eudismic Ratio and its logarithm as the Eudismic Index (EI):

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