Biomedical Engineering Reference
In-Depth Information
5
Stereochemistry
in Drug Design
Maria B. Mayo-Martin and David E. Jane
CONTENTS
5.1 Introduction ........................................................................................................................... 76
5.2 What Is Chirality .................................................................................................................. 76
5.3 The Origin of Stereospecii city in Molecular Recognition................................................... 78
5.4 Why Is Stereochemistry Important in Drug Design............................................................. 79
5.4.1 The Distomer Is Inactive (High ER)........................................................................ 80
5.4.2 Both Enantiomers Have Independent Therapeutic Benei ts .................................... 80
5.4.3 Distomer Possesses Harmful Effects....................................................................... 81
5.4.4 The Eutomer and the Distomer Have the Opposite
Biological Activity ................................................................................................... 81
5.4.5 The Racemate Has a Therapeutic Advantage over the
Individual Enantiomers............................................................................................ 81
5.4.6 One Enantiomer Is Converted into the Other in the Body ...................................... 82
5.5 Methods for Obtaining Pure Stereoisomers.......................................................................... 83
5.5.1 Resolution of Racemates by Crystallization of Diastereomers ............................... 83
5.5.2 Enantioselective Chromatography ........................................................................... 84
5.5.2.1 Ligand Exchange ...................................................................................... 84
5.5.2.2 Crown Ethers............................................................................................ 84
5.5.2.3 Pirkle Columns......................................................................................... 84
5.5.2.4 Miscellaneous Phases............................................................................... 85
5.5.2.5 Simulated Moving Bed Chromatography ................................................ 85
5.5.3 Asymmetric Synthesis ............................................................................................. 85
5.5.3.1 The Chiral Pool ........................................................................................ 85
5.5.3.2 Stereoselective Synthesis.......................................................................... 85
5.5.3.3 The Use of a Chiral Auxiliary ................................................................. 85
5.5.3.4 The Use of Chiral Reagents and Catalysts............................................... 86
5.5.3.5 The Use of Enzymes and Whole Organisms ........................................... 86
5.6 Analytical Methods of Determining Purity of Stereoisomers.............................................. 87
5.6.1 Nuclear Magnetic Resonance Spectroscopy............................................................ 87
5.6.2 Gas Chromatography ............................................................................................... 87
5.6.3 Capillary Electrophoresis ........................................................................................ 88
5.6.4 Mass Spectrometry .................................................................................................. 88
5.7 Concluding Remarks............................................................................................................. 88
Further Readings.............................................................................................................................. 88
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