This journal is © The Royal Society of Chemistry 2015 Chem. Soc. Rev. Cite this: DOI: 10.1039/c4cs00477a Pharmaceuticals that contain polycyclic hydrocarbon scaffolds Tegan P. Stockdale and Craig M. Williams* Numerous variations on structural motifs exist within pharmaceutical compounds that have entered the clinic. These variations have amounted over many decades based on years of drug development associated with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approximately 20 all carbon cage containing pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs containing the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurological activity. In addition, to an extensive overview of the history and biology associated with each drug, a survey of synthetic methods used to construct these entities is presented. An analysis section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs. 1. Introduction Many different structural motifs exist within pharmaceutical compounds, which arise from decades of screening and evaluating natural products 1 and synthetic entities. 2,3 A structure may be as simple as the antibacterial agent acetic acid or as complex as a chemotherapeutic natural product, such as paclitaxel (1) (Fig. 1). That considered, the structure and functional groups incorporated into a drug determine not only molecular recognition at the target site, but also broader pharmacological properties, such as membrane permeability, selectivity and susceptibility to meta- bolic processes [i.e. absorption, distribution, metabolism, and excretion (ADME)]. This premise alone has been the topic of many wide ranging review articles in drug discovery. 4–8 Reviews targeting specific functional groups and structural motifs within drugs and drug discovery have also appeared; 9,10 however, a survey covering approved pharmaceutical compounds incor- porating polycyclic hydrocarbon scaffolds seems not to have been undertaken. Polycyclic hydrocarbon, caged bicyclic (or bridged bicyclic) scaffolds or motifs are simply defined as an atomic bridge appended across an underlying ring of atoms connected at bridgeheads (see extracted systems 2 and 4 in Fig. 1). Such systems offer a variety of diverse structures, encompassing three-dimensional shape and assorted pharmaco- kinetic properties, often attributed to their hydrocarbon nature. They can differ substantially in size, and the identity of the atoms that compose the cage skeleton, which is a substantial sideways shift away from planar systems. 11 These features have facilitated a wide spectrum of approved pharmaceutical applications Fig. 1 Paclitaxel (1) and buprenorphine (3) and their corresponding polycyclic hydrocarbon core structural elements 2 and 4. School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, 4072, Qld, Australia. E-mail: c.williams3@uq.edu.au Received 12th December 2014 DOI: 10.1039/c4cs00477a www.rsc.org/chemsocrev Chem Soc Rev REVIEW ARTICLE Published on 14 July 2015. Downloaded by University of Queensland on 24/07/2015 01:48:40. View Article Online View Journal