Bicyclo[2.2.2]octane (BCO) as a 3D-Rich Bioisostere for the para-Phenyl Group

Along with bicyclo[2.2.2]pentane (BCP) and cubane (CUB), bicyclo[2.2.2]octane (BCO) is one of the three prominent 3-D isosteres for the 2-D phenyl ring. Since BCO has all sp 3 carbons, it could potentially offer several advantages over the flat phenyl group, including possible better binding with the targets, thus higher potency, better selectivity, thus lower promiscuity and lower toxicity, and potentially improved solubility as a consequence of disrupting aromaticity. However, BCO is three-carbon larger and more lipophilic than the bicyclo[2.2.2]pentyl group (BCP). It is sometimes beneficial to consider using BCP in place of BCO as the bioisostere of a para- phenyl group.