Drugs enantiomeric forms

Section 7 8 Both enantiomers of the same substance are identical m most of then-physical properties The most prominent differences are biological ones such as taste and odor m which the substance interacts with a chiral receptor site m a living system Enantiomers also have important conse quences m medicine m which the two enantiomeric forms of a drug can have much different effects on a patient... 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

The antiviral activity spectrum of the ddN analogues should, in principle, extend to all retroviruses as well as hepadnaviruses [i.e., hepatitis B virus (HBV)], since HBV, like retroviruses, replicates through an RNA template-driven RT process. Indeed, various ddN analogues (particularly, the L-enantiomeric forms 3TC, FTC, and L-DDC) have been shown to inhibit HBV replication [36-38]. Consequently, 3TC is, at present, pursued as a potential drug candidate for the treatment of both HIV and HBV infections. 

The quantitation of undesired enantiomers in drug raw materials is one of the objectives of the pharmaceutical industry. Several calixarene derivatives were investigated as fluorescence sensors for chiral pharmaceutical compounds. The mechanism of these examples is based on different fluorescence quenching of the calixarenes by the two enantiomeric forms of a specific analyte. 

In other words, different reactivities with the enantiomeric forms of chiral substrates or drugs, binding at the same site, would not be observed in the absence of diastereoisomeric possibilities. This is really another way of expressing three-point attachment. If the enzyme or receptor is chiral, then the classical three- and two-point arrangements 11 and 12, are, of necessity, diastereoisomeric. 

In retrospect, Cushny was one of the earliest investigators to point out the diastereoisomeric situations which occur when a chiral biopolymer interacts with the enantiomeric forms of another molecule. The three-point attachment and polyaffinity concepts provided an easily visualized picture of how the differentiation might occur. For a time, unfortunately, the possibility of differentiation by a one-point approach was not clearly recognized and three-point attachment became somewhat dogmatic. With more detailed structural investigations, it is becoming clear that interactions between enzymes and substrates, and receptors and drugs, often involve a multiplicity of interactions. 

In this case, the achiral reagents reacting via an achiral (or racemic) intermediate in an achiral solvent should produce racemic product. Over 40 years ago, this is all we could expect of such a reaction in terms of stereoselectivity. If the purpose of the transformation was to obtain one or the other enantiomer, then special and often tedious methods were required to resolve the racemic product. Today, the goal of synthesis chemists often is to produce molecules that are not only chiral, but also enantiomerically pure. Biologically active molecules typically exist in only one enantiomeric form. Efficacious drugs are also often most effective if they exist as only one enantiomer in order to interact properly with a chiral active site. A racemic drug is a mixture of enantiomers, only 50% of which is usually efficacious. The other 50% is at best worthless and at worst toxic, sometimes severely so.2... 

Chiral molecules are characterized by three-dimensional handedness and can exist in two enantiomeric forms of opposite absolute configuration (AC). Most natural products and biologically active compounds are chiral and their biological and molecular functions are closely related to their chirality, that is, AC and conformation. Furthermore, many drugs derived from natural products or of purely synthetic origin are currently used in enantiopure form. Therefore, the unambiguous determination of the AC of chiral compounds is critical for the studies of natural products and biomolecular systems.1... 

We now address the question Why separate enantiomers What is the compelling reason for resolving racemic mixtures anyway For many years there was little impetus to separate enantiomers other than for the sake of knowledge scientists were simply interested in studying the behavior of these stereoisomers in different environments. In the industrial sector there was no reason to separate enantiomers. Even in the pharmaceutical business where it was recognized that the enantiomeric forms of chiral drugs can, and usually do, behave differently there was little focus on chiral synthesis and even less on chiral separations until recently. 

The manufacture of fine chemicals, particularly drugs, fragrances, and flavors, is undergoing a major revolution now as a result of the capability of chemists to prepare these chemicals, mainly drugs, in their purest isomeric forms (as stereoisomers). This shift to pure forms has been described by Brown in the following words (1990) (see also Deutsch, 1991) A mixture of stereoisomers in a medicine will (now) need to be justified just the same way as any other mixture of compounds. Indeed, in the United States today (as in many other advanced countries), the use of pure enantiomeric forms is practically a requirement since extensive justification is needed to continue with racemates (FDA, 1992). As a consequence, the combined sales of the chiral top ten drugs (ammoxydllin, enalapril, ampicillin, captopril, pravastatine, diltiazem, ibuprofen, lovastatin, naproxen, and fluoxetine) in 1994 amounted to more than 16 billion dollars (Sheldon, 1996). (Of these, ibuprofen and fluoxetine are still sold as racemates.)... 

Because patent expiry for a racemate tends to proliferate the drug as generics, product line extension for an existing racemate technology can be obtained by switching to a single stereoisomeric form (the racemic switch). This is an incentive to produce the drugs in their pure enantiomeric forms. 

SECTION 24.5 Molecules that possess nonsuperimposable mirror images are termed chiral. The two nonsuperimposable forms of a chiral molecule are called enantiomers. In carbon compounds a chiral center is created when all four groups bonded to a central carbon atom are different, as in 2-bromobutane. Many of the molecules occurring in living systems, such as the amino acids, are chiral and exist in nature in only one enantiomeric form. Many drugs of importance in human medicine are chiral, and the enantiomers may produce very different biochemical effects. For this reason, synthesis of only the effective isomers of chiral drugs has become a high priority. 

The anti-inflammatory drug, ibuprofen, exists in two enantiomeric forms which also can be separated on open tubular columns coated with derivatized P-cyclodextrin. An example of the separation of the isomers of ibuprofen is shown in figure 6.15. 

This material is synthesized from 4-(3,5-dinitrobenzamido)-tetrahydro-phenanthrene which is also covalently bonded to silica particles 5 pm in diameter. It is used to separate the underivatized isomers of drugs such as Ibuprofen and Naproxen. It is a fairly stable phase and is available in both enantiomeric forms allowing elution order reversal if so desired. 

Chirality is generally only a problem in clinical applications when the assay involves a comparatively small molecule, such as a drug or a small synthetic peptide. Antibodies, like most biological reagents, exhibit handedness or chiral specificity. Therefore, where the analyte occurs as a mixture of enantiomeric forms, only one enantiomer may bind to the antibody, or different enantiomers may bind with different affinities. The relevance of the standard depends on whether it is presented as a pure enantiomeric form, or as a mixture of enantiomers that reflects the composition of the analyte. 

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