Cubane as a Bioisostere of Benzene

In 1964, the late Philip Eaton successfully synthesized cubane, a molecule once thought impossible. And then in 1992, Eaton announced that cubane should be considered more than novelty. He suggested that cubane could be used to replace benzene in pharmaceuticals to improve the pharmacokinetic properties of the parent drug. Following this announcement, cubane was only seen sporadically in the literature. But then thirty-four years later, this hypothesis was validated when a set of pharmaceuticals were compared to their cubane isosteric counter parts.

Both cubane and benzene are similar in size, cubane having a diagonal width of 2.72Å, while benzene has a width of 2.79Å. Even more importantly to drug design, the bond angles of the substituents on benzene and cubane are oriented almost identically. This similarity allows for cubane to be substituted for benzene.

Isosteres were first defined in 1919 by Irving Langmuir as “compounds or groups of atoms having the same number of electrons”. And then in 1951, Harris Friedman coined the term bioisostere. Describing “atoms or molecules that fit the broadest definition for isosteres and have the same biological activity” as bioisosteres. Further broadening this concept, C. W. Thomber listed the biological properties that could be modulated by replacing fragment(s) of a parent drug. In drug design, this has traditionally been switching a fluorine for a hydrogen to combat metabolism concerns or replacing a benzene for a pyridine to improve solubility.