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Medicinal chemistry of polycyclic cage compounds in drug discovery research

Abstract

Saturated polycyclic hydrocarbon structures such as the monocyclic octane, bicylic norbornane and tricyclic adamantane have attracted the attention of several research groups since the 1930s. In the 1950s the synthesis of the so called bird-cage pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione, also known as Cookson’s diketone was reported. This pentacyclic cage diketone is the product of the intramolecular photocyclized Diels Alder adduct of p-bensoquinone and cyclopentadiene. The conversion of this diketone to its monoketone analog formed the basis of a variety of monosubstituted derivatives. Furthermore, acid-based rearrangement reactions of hydroxyl-substituted compounds led to, amongst others, the unique D3-trishomocubane symmetrical compounds, which consists of only five-membered carbon rings. The D3 stereoisomerism of the trishomobubane affords unique chemical challenges with potential medicinal implications. The medicinal chemistry of these cage compounds gained momentum in the 1980s with the discovery of the calcium-channel-modulating effects and antiviral activity thereof. The 1990s and 2000s saw several reports on a variety of pharmacological areas, i.e., dopaminergic, catecholaminergic, and focusing on disorders, in particular that of the central nervous system, such as neurodegeneration (Parkinson’s disease). These polycyclic structures have proved to be very useful in drug discovery research, in particular during the past 25 years.

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Acknowledgements

The South African National Research Foundation (NRF) is thanked for financial support. Mrs. Hannelie Viviers is thanked for her most valuable assistance in the technical support of this manuscript.

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Correspondence to Douglas W. Oliver.

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Oliver, D.W., Malan, S.F. Medicinal chemistry of polycyclic cage compounds in drug discovery research. Med Chem Res 17, 137–151 (2008). https://doi.org/10.1007/s00044-007-9044-5

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Keywords

  • Synthesis
  • Drug discovery
  • Brain and antiviral activities
  • Polycyclic, Pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione
  • D3-trishomocubane