Drug molecules chirality

The two forms of mirror images are called enantiomers, or stereoisomers. All amino acids in proteins are left-handed, and all sugars in DNA and RNA are right-handed. Drug molecules with chiral centers when synthesized without special separation steps in the reaction process result in 50/50 mixtures of both the left- and right-handed forms. The mixture is often referred to as a racemic mixture. 

Omeprazole and esomeprazole. The two S atoms are chiral centers. Source Agranat I, Caner H, Caldwell J. Putting chirality to work the strategy of chiral switches of drug molecules, Nature Reviews Drug Discovery 1 753-768 (2002). Used with permission.)... 

The chiral separation of drug molecules and of their precursors, in the case of the synthesis of enantiomerically pure drugs, is one of the important application areas of HPLC in pharmaceutical analysis. Besides HPLC, capillary electrophoresis is another technique of choice for chiral separations. In this chapter we give an overview of the different modes (e.g., direct and indirect ones) by which it is possible to obtain a chiral separation in HPLC and CE. The direct approaches, i.e., those where the compound of interest is not derivatized prior to separation, are discussed in more detail since they are the most frequently used... 

The first report in this regard described a method for direct formation of the desired optically active (S)-alcohol 32a, via enantioselective reduction with a chiral amine complex of lithium aluminum hydride (Scheme 14.9). Therefore, the necessary chiral hydride complex 38 was preformed in toluene at low temperature from chiral amino alcohol 37. The resulting hydride solution was then immediately combined with ketone 31 to afford the desired (S)-alcohol 32a in excellent yield and enantiomeric excess. In addition to providing a more efficient route to the desired drug molecule, this work also led to the establishment of the absolute configuration of duloxetine (3) as S). 

Optical isomerism of drug molecules is widespread. Many drug molecules only contain one or two chiral centres. A simple example is the naturally occurring neurotransmitter adrenaline. When a compound has no symmetry about a particular carbon atom the carbon atom is said to be a chiral centre. When a compound contains one or more chiral centres it is able to rotate plane-polarised light to the right (+) or the left (-). A chiral centre arises when a carbon atom has four structurally different groups attached to it. 

Figure 1.6 Properties of a drug molecule. A drug has many properties (size, shape, topology, polarity, chirality) that influence its ability to interact with a receptor. Each of these properties is required for the unique pharmacological activity of a drug molecule.

There is currently a growing awareness amongst pharmacologists of the importance of stereochemistry, particularly of the chirality of drug molecules. These drugs may be coordination complexes, ligand molecules with potential for in vivo coordination, or molecules whose in vivo interactions are unknown. 

The shape of a drug molecule must be such as to permit binding to its receptor site. Optimally, the drug s shape is complementary to that of the receptor site in the same way that a key is complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so... 

Answer Only one of the two enantiomers of the drug molecule (which has a chiral center) is physiologically active, for reasons described in the answer to Problem 3 (interaction with a stereospecific receptor site). Dexedrine, as manufactured, consists of the single enantiomer (D-amphetamine) recognized by the receptor site. Benzedrine was a racemic mixture (equal amounts of D and l isomers), so a much larger dose was required to obtain the same effect. 

A clear three-dimensional visualization of the means by which a receptor could differentiate between enantiomers was provided by Easson and Stedman in 1933 [25]. They proposed that three (b, c, d) of the four groups (a, b, c, d) linked to a chiral carbon atom were concerned in the process (either by normal valence forces, or by adsorptive or other forces). The receptor possessed three groups b, c and d for maximum physiological effect, the drug molecule must become attached to the receptor in such a manner that the groups b, c and d in the drug coincide respectively with b, c and d in the receptor. Such coincidence can only occur with one of the enantiomorphs and this consequently represents the more active form of the drug . The interaction (5) and non-interaction (6) were illustrated as follows ... 

Chirality plays a major role in biological processes and enantiomers of a particular molecule can often have different physiological properties. In some cases, enantiomers may have similar pharmacological properties with different potencies for example, one enantiomer may play a positive pharmacological role, while the other can be toxic. For this reason, advancements in asymmetric synthesis, especially in the pharmaceutical industry and life sciences, has led to the need to assess the enantiomeric purity of drugs. Chromatographic chiral separation plays an important role in this domain. Today, there are a large number of chiral stationary phases on the market that facilitate the assessment of enantiomeric purity. 

A living organism is a sea of chiral molecules. Many drugs are chiral, and often they must interact with a chiral receptor or a chiral enzyme to be effective. One enantiomer of a drug may effectively treat a disease whereas its mirror image may be ineffective. Alternatively, one enantiomer may trigger one biochemical response and its mirror image may elicit a totally different response. 

In principle, nanotubes with the Cig inside extract any lipophilic molecule. This ability to sequester lipophilic molecules can be viewed as a generic type of extraction selectivity, which might be useful in some apphcations. However, nanotubes that have molecular-recognition capability and extract only one particular molecule from solution might also be useful. We have shown that antibody-functionalized nanotubes can provide the ultimate in extraction selectivity—the extraction of one enantiomer of a chiral drug molecule. 

Most optically active drugs are chiral as a result of the presence of an asymmetrically substituted tetrahedral carbon atom. However, chirality can result from the presence of other asymmetrically substituted atoms within molecules as illustrated below including phosphorous (Fig. 5), nitrogen (Fig. 6), and sulfur (Fig. 7). 

---