Pharmaceuticals, Chiral

Abstract

Stereospecific structure-activity relationships are of sufficient complexity to warrant a clear understanding of the terms involved. Prior to discussing these relationships the following definitions are offered. Stereoisomers are compounds which have the same molecular formula but differ in the arrangement of their atoms in space. Chiral compounds are compounds which have nonsuperimposable mirror images. Enantiomers are pairs of stereoisomers which are nonsuperimposable mirror images; they possess identical physical and chemical properties within an achiral environment. Stereoisomers other than enantiomers, ie, diastereomers, are identified by distinct physical and chemical properties including melting points, spectral characteristics, and rates of reaction with both chiral and achiral reactants. Enantiomers, however, are only distinguished when in the presence of a homochiral environment such as polarized light, chiral solvents, chiral reagents, or chiral molecules such as biomolecules, eg, nucleic acids (qv), proteins (qv), and carbohydrates (qv). The two molecules in a pair of enantiomers rotate a plane of polarized light with equal intensities, but in opposite directions. The dextrorotatory isomer (+ or d) rotates the plane of polarized light clockwise; the levorotatory isomer (− or l) rotates the plane of polarized light counterclockwise. An equal mixture of (+ ) and (−)-enantiomers is a racemic mixture or racemic compound and does not rotate a plane of polarized light. Optical rotation, an intrinsic property of the substance, has no bearing on drug-macromolecule interactions. It is the absolute configuration of the homochiral compound that is important for its interaction with biomolecules.Absorption, metabolism, and biological activities of organic compounds are influenced by molecular interactions with asymmetric biomolecules. These interactions, which involve hydrophobic, electrostatic, inductive, dipole-dipole, hydrogen bonding, van der Waals forces, steric hindrance, and inclusion complex formation give rise to enantioselective differentiation (1, 2). Within a series of similar structures, substantial differences in biological effects, molecular mechanism of action, distribution, or metabolic events may be observed. For example, (R)-carvone [6485-40-1] (1) has the odor of spearmint whereas (S)-carvone [2244-16-8] (2) has the odor of caraway (3, 4).