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.
Similar content being viewed by others
References
Carpy AJM, Oliver DW (1994) 3-Phenyl-D3-trishomocuban-4-ol: structure and configuration. Helv Chimica Acta 77:543–546
Chakrabarti JK, Hotten TM, Sutton S, Tupper DE (1976) Adamantane and protoadamantanealkanamines as potential anti-Parkinson agents. J Med Chem 19(7):967–969
Cookson RC, Grundwell W, Hudec (1958) Synthesis of cage-like molecules by irradiation of Diels-Alder adducts. J Chem Ind 1003–1004
Davies WL, Grunert RR, Haff RF, McGahen JW, Neumayer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffman CE (1964) Antiviral activity of adamantamine. Science 144:862–863
Dekker TG, Oliver DW (1979) The synthesis of (D3)-trishomocuban-4-ol via carbenium ion rearrangements of pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8-ol. S Afri J Chem 32:45–48
Dekker TG, Oliver DW, Venter A (1980) 1-Methyl-(D3)-trishomocubane. Tetrahedron Lett 21:3101–3104
Eaton PE, Hudson RA, Giodano C (1974) Trishomocubanone (pentacyclo[6.3.0.02,6.03,10.05,9]undecan-4-one). J Chem Soc Chem Commun 987–991
Geldenhuys WJ, Malan SF, Murugesan T, Van der Schyf CJ, Bloomquista JR (2004) Synthesis and biological evaluation of pentacyclo[5.4.0.02,6.03,10.05,9]undecane derivatives as potential therapeutic agents in Parkinson’s disease. Bioorg Med Chem 12:1799–1806
Geldenhuys WJ, Malan SF, Bloomquist JR, Van der Schyf CJ (2007) Structure–activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor. Bioorg Med Chem 15:1525–1532
Godleski SA, Schleyer P von R, Osawa E, Kent GJ (1974) Syntheses of (D3)-Trishomocubane (Pentacyclo[6.3.0.02,6.03,10.05,9]undecane) by Rearrangement. J Chem Soc Chem Commun 976–977
Griffin GW, Marchand AP (1989) Synthesis and chemistry of cubanes. Chem Rev 89: 977–1010
Grobler E, Grobler A, Van der Schyf JC, Malan SF (2006) Effect of polycyclic cage amines on the transmembrane potential of neuronal cells. Bioorg Med Chem 14:1176–1181
Kent GJ, Godleski SA, Osawa E, Schleyer P Von R (1977) Synthesis and relative stability of (D3)-trishomocubane (pentacyclo[6.3.0.02,6.03,10.05,9]undecane), the pentacycloundecane stabilomer. J Org Chem 42:3852–3859
Larrick JW, Lipton SA, Wang Y, Ye W, Stemler JS (2002) US patent no. US6444702
Lenoir D, Glaser R, Mison P, Schleyer Pvon R (1971) Synthesis of 1,2- and 2,4-disubstituted adamantanes. The protoadamantane route. J Org Chem 36: 1821–1826
Malan SF, Van den Heever I, Van der Schyf CJ (1996) Screening of polycyclic amines for calcium channel activity. J Pharm Med 6:125–135
Malan SF, Dockendolf G, Van der Walt JJ, Van Rooyen JM, Van der Schyf CJ (1998) Enantiomeric resolution of the calcium channel antagonist 8-benzylamino-8,11-oxapentacyclo[5.4.0.02,6.03,10.05,9]undecane (NGP1–01). Pharmazie 53:859–862
Malan SF, Van der Walt JJ, Van der Schyf CJ (2000) Structure–activity relationships of polycyclic amines with calcium channel blocking activity. Arch Pharm Med Chem 333:10–16
Malan SF, Dyason K, Wagenaar B, Van der Walt JJ, Van der Schyf CJ (2003) The structure and ion channel activity of 6-benzylamino-3-hydroxyhexacyclo[6.5.0.03,7.04,12.05,10.09,13] tridecane. Arch Pharm Med Chem 336:127–133
Marchand AP, Arney BE, Dave PR (1988) Transannular cyclizations in the pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione system: a reinvestigation. J Org Chem 53:2644–2647
Marchand AP (1989) Synthesis and chemistry of homocubanes, bishomocubanes and trishomocubanes. Chem Rev 89:1011–1033
Marchand AP (1989) In: Advances in theoretically interesting molecules, Vol. 1. Greenwich, CT: JAI, Thummel RP 357–399
Marchand AP (1995) Polycyclic cage compounds: reagents, substrates, and materials for the 21st century. Aldrichimica Acta 28:95–104
Nakazaki M (1984) The synthesis and stereochemistry of chiral organic-molecules with high symmetry. Top Sterochem 15:199–251
Oliver DW, Dekker TG (1988) (D3)-Trishomocubane stereoisomerism. S Afri J Sci 84:407–409
Oliver DW, Dekker TG, Snyckers FO (1991) Pentacyclo[5.4.0.02,6.03,10.05,9]undecylamines. Synthesis and pharmacology. Eur J Med Chem 26:375–379
Oliver DW, Dekker TG, Snyckers FO (1991) Antiviral properties of 4-amino-(D3)-trishomocubanes. Arzneimittel-Forschung/Drug Res 41:549–552
Oliver DW, Dekker TG, Snyckers FO, Fourie TG (1991b) Synthesis and Biological Activity of D3-Trishomocubyl-4-amines J Med Chem 34:851–854
Oliver DW, Dekker TG, Wessels PL (1994) Stereochemistry of 4-amino-(D3)-trishomocubanes. NMR study of 3-phenyl-4-amino-(D3)-trishomocubane. Magnetic Res Chem 32:330–334
Oliver DW, Carpy AJM (1995) Crystallographic evidence for the stereospecific synthesis of 4-amino-(D3)-trishomocubanes: crystal structure of 3-methyl-(D3)-trishomocubane-4-amine hydrocholoride hydrate. Zeitsch für Kristall 210:861–864
Schwab RS, England AC Jr, Poskanzer DC, Young RR (1969) Amantadine in the treatment of Parkinson’s disease. J Am Med Assoc 208(7):1168–1170
Singh V, Thomas B (1998) Recent developments in general methodologies for the synthesis of linear triquinanest. Tetrahedron 54:3647–3692
Stamatiou G, Foscolos GB, Fytas G, Kolocouris N, Pannecouque C, Witvrouw M, Padalko E, Neyts J, De Clercq E (2003) Heterocyclic rimantadine analogues with antiviral activity. Bioorg Med Chem 11:5485–5492
Underwood GR, Ramamoorthy B (1970) Chemical studies of caged compounds. II. The synthesis of pentacyclo[6.3.0.02,6.03,10.05,9]undecane: Trishomocubane. Tetrahedron Lett 11:4125–4127
Van der Schyf CJ, Dekker TG, Snyckers FO (1986) Pharmacological studies of two novel polycyclic derivatives of ephedrine. Arch Pharm (Weinheim) 319(5):409–415
Van der Schyf CJ, Liebenberg W, Bornman R, Dekker TG, Van Rooyen PH, Fourie TG, Matthee E, Snyckers FO (1989) The polycyclic calcium antagonist, NGP1–01, has an oxa rather than an aza bird-cage structure: evidence from n.m.r. spectroscopy and the X-ray crystal structure. S Afr J Chem 42:42–46
Wesemann W (1983) Wirkung einer polyzyklischen Verbindungsklasse mit diamant/ihnlicher Struktur. Funkt Biol Med 2:137–145
Zah J, Terre’Blanche G, Erasmus E, Malan SF (2003) Physicochemical Prediction of a Brain-Blood Distribution Profile in Polycyclic Amines. Bioorg Med Chem 11:3569–3578
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-007-9044-5