Thursday, February 18, 2016

Enantiomers: Exactly the Same… Only, Different!



By Jim Schmidt
Senior Scientific Advisor
ABC Laboratories

In chemistry, enantiomers are stereoisomers that are non-superimposable mirror images of each other - much like your left and right hands are the same except for being reversed along one axis.

*Image courtesy of Wikimedia Commons


Indeed, the study of enantiomers – chirality – comes from the Greek word, “Χειρ = Cheir =  Hand”!

Enantiomers have identical chemical and physical properties except for their ability to rotate plane-polarized light by equal amounts but in opposite directions.

However, in biological systems, they can have very different behavior.  Some of the most interesting – and important – differences are in drug metabolism.

For the better part of a century, the consideration of enantiomers in drug metabolism was limited to academic study and/or to natural products, owing in no small part to the limits of separations chemistry.

However, for many reasons (including improvements in analytical chemistry), chirality has been earning ever-greater importance in drug discovery and development, such that many new drugs reaching the market in the first decades of the 21st century are single enantiomers, rather than the racemic mixtures (or achiral drugs) that dominated the latter half of the 20th century.

Indeed, in the recent report, “The Year in New Drugs” (C&E News, February 1, 2016, pp. 12-17), it can be seen that more than half of the newly-approved small-molecule drugs in 2015 had specific stereochemistry (and often with more than one chiral center).

Examples of enantio-selective biotransformations include:
  • Prochiral to Chiral 
  • Chiral to Chiral 
  • Chiral to Achiral 
  • Chiral to Diastereoisomer 
  • Chiral Inversion

These metabolism pathways can have significant effects on pharmacology and drug safety. While the movement towards single enantiomers as drug candidates, noted above, mitigates safety problems that might  be associated with racemic mixtures, they do not necessarily alleviate the need to consider and study achiral-to-chiral, chiral-to-chiral, and/or chiral-to-diastereomer transformations.

Adapted from my chapter – “Metabolite Profiling” – in New Horizons in Predictive Drug Metabolism and Pharmacokinetics (edited by Alan G. E. Wilson; Royal Society of Chemistry, 2015).

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