“Atropisomeric” Drugs: Basic Concept and Example of Application to Drug Development ()
Cite this paper
Atropisomerism relates to chemical structures that contain at least two rings linked by a single bond. Normally, the free-energy
“Atropisomeric” Drugs: Basic Concept and Example of Application to Drug Development ()
Cite this paper
Atropisomerism relates to chemical structures that contain at least two rings linked by a single bond. Normally, the free-energy of rotation is very low in such cases, so the rings are free to rotate about the axis of the bond. But if the rings have constituent groups sufficiently large, bulky, or otherwise repulsive, rotation can be inhibited, and create asymmetry. This situation gives rise to distinct non-interconvertible forms that are “rotational isomers” termed “atropisomers” (from the Greek for the unturning, after the eldest of the three Fates ætropoç, Atropos). The first atropisomers were identified for the compound 6,6'-Dinitro-2,2'-diphenic acid (Figure 1).
Figure 1. 6,6'-Dinitro-2,2'-diphenic acid. The two aromatic rings are joined by a single bond, which would normally allow the rings to rotate freely around the axis of the bond. But the carboxyylic and nitro groups sterically interfere with rotation, leading to non-superimposable “atropisomers”. Top: usual representation of chemical structure; Bottom: heavy lines indicate that the aromatic ring is not planar.
Some examples of naturally-occurring atropisomers that have medicinal properties and are used in pharmacotherapeutic applications include the relatively small chemical structure of the selective inhibitor of leukotriene metabolism knipholone (Figure 2)  obtained from the roots of the tropical ferns Kniphofia foliosa to the very large chemical structure of the antibiotic vancomycin (Figure 2)  obtained from the soil bacterium Amycolatopsis orientalis (Streptomyces orientalis).
2. Relation to Drug Development
Chirality is of well-recognized importance in medicinal chemistry and drug development because mirror-image molecules often have clinically significantly different pharmacologic properties  . The enantiomers of a chiral drug can differ in pharmacodynamics or any aspect of ADME (absorption, distribution, metabolism, or elimination). And each of the enantiomers can be pharmacologically inert, or contribute (additively, synergistically, or sub-additively) to the drug’s therapeutic effect or adverse effects. If one enantiomer does not significantly contribute to the desired pharmacologic effect, it has been called “isomeric ballast” . Widely-used drugs that benefit from the contribution of both enantiomers are the analgesic tramadol    and the antidepressant fluoxetine  . A particularly tragic example of a negative contribution of an enantiomer to a drug is thalidomide  .
In the case of compounds with classical chiral centers, interconversion of enantiomers requires bond-breaking. In contrast, in the case of atropisomers, interconversion involves only rotation around a bond (Figure 3). Thus, for atropisomers, the question becomes one of relative stability of the two forms. That is, the greater the steric hindrance inhibiting free rotation, the more stable—and less interconvertible—the individual forms (Figure 4). The relevant stability for 