Academic Supplement Single-Isomer Science: The Phenomenon and Its Te rm i n o l o g y By Joseph Gal, PhD ABSTRACT For more detailed information, the reader is re f e rred to text- Single-isomer drugs are of great importance in modern books of basic organic chemistry; advanced treatments of therapeutics. In this article, the basics of the underlying the subject are also available, including an excellent mono- phenomenon are explained. Some molecules are chiral, ie, g r a p h 3 and a highly informative and entertaining volume on their mirror image is not superposable on the original. The a broad variety of aspects of the phenomenon.4 most common element producing molecular chirality is a chiral center, typically a carbon atom carrying four diff e r- MIRROR, MIRROR ON THE WALL... ent groups. The mirro r-image molecules are termed e n a n- C e rtain objects have the pro p e rty that their mirror image t i o m e r s , but the less specific terms s t e r e o i s o m e r s a n d is not entirely identical with the original. The most familiar isomers are also used. A substance consisting of only one of tools for the illustration of this phenomenon are the two the two enantiomers is a single enantiomer or single iso- human hands. If one holds, say, the left hand in front of a m e r, and the 1:1 mixture of the enantiomers is the racemic m i rro r, one finds that the image in the mirror is that of the m i x t u re or racemate. A graphical convention that conveys right hand. Clearly, the right hand is the mirror image of the the three-dimensional aspects of chiral molecules drawn in left hand, and vice versa. Furt h e rm o re, while the two hands two dimensions, as well as two nongraphical conventions, of an individual are identical in appearance, one cannot based on optical rotation and configuration, are used to “ m e r ge” perfectly the left hand into the right one (or the identify enantiomers. Optical rotation is a physical pro p- right hand into the left). This is in contrast to the mirro r e r ty of single enantiomers and involves rotation of the image of another kind of object, eg, the cue ball used in bil- plane of plane-polarized light, each pure enantiomer rotat- l i a r ds. The mirro r-image of the ball is identical in all ing with equal magnitude but in the opposite dire c t i o n respects to the original and is indistinguishable from it. (dextro and levo). Configuration is the actual arrangement F u rt h e rm o re, the mirror image of the ball can be fully and in space of the atoms of chiral molecules. Two systems of p e rfectly “merged” into the original. Thus, the mirror image indicating configuration are in use. One employs D and L of the ball is superposable on the original, while the mirro r to denote the respective enantiomers, and is applicable only image of a hand is not superposable on its original. to α-amino acids and carbohydrates. The other is a univer- An object whose mirror image is not superposable on the sal system using R and S as descriptors for the two possible original is termed c h i r a l (ch p ronounced as k and the word a r rangements, re s p e c t i v e l y, of the atoms around the chiral rhymes with viral), and the phenomenon is called c h i r a l i t y, c e n t e r. Interest in chiral drugs stems from the fre q u e n t l y f rom χειρ (cheir), the Greek word for the hand. H a n d e d n e s s o b s e r ved biological diff e r ences between enantiomers. Such is also a useful term to refer to the phenomenon of chirality. enantioselectivity is the result of diff e rent interactions of Chiral objects abound in nature—indeed, the presence of the drug enantiomers with target receptors that are them- chirality ranges from the subatomic to the macro s c o p i c selves chiral and single-enantiomeric. w o r l d . 4 , 5 M a c r oscopic chiral objects include, for example, C N S S p e c t ru m s . 2002;7(suppl 1):8-13 anatomical parts—eg, the hands, feet, and ears—and some c o rresponding clothing items—eg, gloves and shoes— are INTRODUCTION also chiral. Helical or spiral stru c t u res also have handed- Single-isomer drugs have assumed a great deal of impor- ness, eg, screws are chiral, one form having a left-handed tance in recent years, and are poised to become even more t h read and its mirror image a right-handed thread. Helical significant in the future . 1 , 2 The foundation of single-isomer sea shells, similarly, have right-handed or left-handed helic- d rugs is a chemical phenomenon involving the thre e - d i m e n- ity and are chiral; in arc h i t e c t u r e, columns with a spiral sional aspects of molecules (stere o c h e m i s t ry), and a thor- design have handedness (Figure 1).6 The umbilical cord is ough appreciation of the basic and clinical sciences of chiral by virtue of its helical vasculature, and it has been single-isomer drugs is not possible without an understand- shown that left-handed helices predominate in at least one ing of the pertinent fundamentals and terminology of the n e w b o rn population.7 phenomenon. The purpose of this article, there f o re, is to H o w e v e r, our concern here is with molecules and dru g s , p rovide a description of the basic relevant concepts and lan- and we must there f o re turn our attention from the world of guage. Naturally, the discussion will be limited in scope and m a c r oscopic chiral objects to the world of molecules and will be aimed at the non-expert in organic stere o c h e m i s t ry. chemical compounds. Interest in chiral drugs stems fro m D r. Gal is professor of medicine, pharm a c o l o g y, and pathology in the Division of Clinical Pharmacology at the University of Colorado School of Medicine in Denver. M e d Works Media 8 April 2002 Academic Supplement the fact that the two mirro r-image forms of such substances merism exist, with chirality being the basis of one type. often differ significantly, even drastically, in their biological Thus, the two mirro r-image chiral molecules can be e ffects (see below). termed stereoisomers, but this term is general and not spe- cific to chirality. The precise term for the two mirro r- MOLECULAR HANDEDNESS image stereoisomers is e n a n t i o m e r ( f r om the Gre e k Some molecules are chiral by virtue of the presence of a enantios, opposite), and should be used for rigorous accu- c h e m i c a l - s t ructural element that produces chirality. The most r a c y. However, stereoisomer is often used in the chirality common structural chiral element producing chirality is a context to refer to enantiomers. Furt h e rm o re, in the phar- carbon atom with a specific pattern of groups connected to it maceutical and pharmacological context, enantiomer is (substitution pattern). When a carbon atom has four diff e re n t often replaced with isomer, an even less specific term chemical groups (substituents) bonded to it, the geometric than stereoisomer but one which has nevertheless come shape of the bonding arrangement is in the form of a tetrahe- into use in re f e rence to the enantiomers of chiral dru g s d ron. For example, in the molecule shown in Figure 2, the because of its more familiar nature and short form. carbon atom carries four substituents––hydrogen (H), fluorine Overall, then, a compound that is made up of only one of (F), chlorine (Cl), and bromine (Br)––and the four bonds point the two possible mirro r-image molecules is often re f e rred to t o w a rd the four corners of a tetrahedron. Such a carbon atom as a single enantiomer, single stere o i s o m e r, or, again, some- in a molecule is called a chiral center, and the molecule in what loosely, as a single isomer. When the chemist synthe- F i g u re 2 is chiral, ie, it can exist in two forms that are non- sizes compounds made up of chiral molecules using superposable on each other and are related as an object and o rd i n a ry chemical reactions, the product obtained is usually its mirror image. An overwhelming majority of chiral mole- the 1:1 mixture of the two enantiomers, called the r a c e m i c cules owe their chirality to the presence of a carbon chiral m i x t u re o r, simply, the r a c e m a t e.