Reading to Learn Activity (4)

Chiral Drugs

What is chirality? chemical properties of diastereomers can differ and it is not unusual for “Chirality” is the property possessed by a them to have different melting and molecule with such spatial arrangement boiling points, refractive indices, of atoms that it cannot superimpose on its solubility, etc. mirror image. The object and mirror- image pair of molecules has the same H OH CH3 ' CH3 1 ' 1 2 H 2 H constituents and structural formula. Their N N relationship with each other is similar to OH H our left and right hands. The carbon atom H H of a simple chiral centre has four different ephedrine pseudoephedrine groups arranged tetrahedrally (Fig. 1). Isomers of such nature are called Fig. 2: The structure of diastereomeric enantiomers. molecules: ephedrine and pseudoephedrine. a a Chiral Chiral centre centre 3. Geometrical isomers are molecules d d with a carbon-carbon double bond b b c c and they are not optically active. When the groups attached to each Fig.1: A chiral molecule with tetrahedral end of the double bond are on the arrangement and its mirror image. same side, the stereoisomer is named as cis-isomer; when the groups are on There are three types of stereoisomers, the opposite sides, the trans-isomer namely enantiomers, diastereomers and designation is used. geometrical isomers. 1. Enantiomers are two stereoisomers Why is chirality important in drug containing asymmetric carbon atoms development? related as non-superimposable object Biological systems like that of human and mirror images. If an beings have been known to exhibit enantiomer rotates polarized light to chirality. This is reflected by the the right or in a clockwise direction, existence of chirality of drug receptor it is said to be the (+) or the areas and the requirement of chiral dextrorotatory isomer. On the other specificity on drugs. In order to hand, if the plane polarized light is understand the biological effect of drugs, rotated to the left or in a we have to distinguish the three main counter-clockwise direction, the phases of their action. The first phase is isomer is called as the (−) or the the initial receptor differentiation phase, levorotatory isomer. Enantiomers where different drugs have different are identical in chemical and physical affinity and tissue specificity due to properties except for the direction of receptor differentiation and distribution rotation of plane polarized light. for the parent compound formed. The 2. Diastereomers are stereoisomers that second phase is the absorption, are not related as object and mirror distribution, metabolism and excretion images. They contain at least two phase, where the type of bioavailability is asymmetric carbon atoms. Unlike determined. The third phase is the enantiomers, the physical and interaction of the drug with the molecular site of action, leading to the observed

147 Reading to Learn Activity (4) therapeutic effect. What drugs in our daily life are chiral? The three phases of action are based on the receptor theory, similar to the Chirality is an essential dimension in lock-and-key hypothesis proposed by the pharmacology. Worldwide sales of famous scientist Emil Fischer. Receptor chiral drugs in single-enantiomer forms molecules in the body are proteins that continue to grow. The commonly used exhibit high affinities for the binding of single-enantiomer drugs are grouped as molecules with certain structures. This is follows: completely analogous to • Cardiovascular disease: enzyme-substrate binding. Mismatching Atorvastatin calcium, Simvastatin, of drug molecules with the targeted Pravastatin sodium and Valsartan receptors may cause undesirable side • Central nervous system: effects such as requirement of higher Paroxetine hydrochloride and dosage and increased toxicity. Sertraline hydrochloride • Respiratory: All pharmacological activity may reside Fluticasone propionate and in one enantiomer. The therapeutic Salmeterol inactive isomer is regarded as an impurity • Hematology: that possesses a different or undesirable Clopidogrel bisulfate pharmacological entity. This situation • Gastrointestinal: may become even more acute if the active Esomeprazole magnesium enantiomer exhibits a low therapeutic • Antibiotic: value or there is clinically significant Amoxicillin and potassium toxicity. A well-known example of clavulanate therapeutic-specific pair is the R- and S-enantiomers of thalidomide (the R and S designation, after Cahn, Ingold and Questions Prelog, is a way of naming enantiomers 1. Classify the following substances by their structures). The R-enantiomer is into chiral and achiral categories. an effective sedative, which is a medication with calming and soothing basket ball effect that relieves anxiety and promotes gloves sleep. However, the S-enantiomer may amino acids cause teratogen formation. A teratogenic enzymes for digesting proteins foetus is one with deficient, redundant, fats misplaced or grossly misshapen parts. pain killer drugs S-Thalidomide was shown to be water responsible for over 2,000 cases of serious birth defects in children born of women 2. Name and draw structures for the who took it during pregnancy. geometric isomers of pent-2-ene. O O 3. 2,3-dihydroxybutanedioic acid H H O O N N (tartaric acid) is a chiral molecule NH HN having both enantiomers and O O O O diastereomers. Draw all possible stereoisomers for the compound and S-Thalidomide R-Thalidomide identify the chiral centres and the Fig. 3: The enantiomers of thalidomide pair(s) of enantiomers.

148 Reading to Learn Activity (4)

4. What are the advantages of providing drugs in enantiomerically pure form? How can single-enantiomeric drugs be obtained in practice?

5. Imagine that you can walk through a mirror into a mirror world where all objects, including atoms and molecules, exist as their mirror images. Assuming that you remain unchanged by this transition, i.e. enzymes in your body are not affected and are still capable of processing molecules in the same way as that in the parent world, what problem would you encounter during your stay in the mirror world? Explain briefly.

Hint: In the mirror world, you would not obtain energy by taking sugar labeled as D-glucose because it is in fact L-glucose, the enzyme-inactive form of glucose.

References 1. Roger Crossley. (1995). Chirality and the Biological Activity of Drugs. Boca Raton: CRC Press Inc.

2. Aboul-Enein & Wainer. (1997). The Impact of Stereochemistry on Drug Development and Use. Wiley International Publication.

3. Hava Caner, Efrat Groner & Liron Levy (2004). Trends in the Development of Chiral Drugs. Drug Discovery Today, Vol. 3 No. 3.

4. Gordon T. Yee (2002). Through the Looking Glass and What Alice Ate There. Journal of Chemical Education, No. 5, Vol. 79, 569 – 571.

5. Dinan F.J. &Yee G.T. (2004). An Adventure in Stereochemistry. Journal of College of Science Teaching, No. 2, Vol. 34, 25 – 29.

6. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a600045.html

7. 芮耀誠 (2002)《實用藥物手冊》香港：中華書局。

8. http://www.atchem.net/Catalogalphabetic/cf_cz.HTM

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