Journal of Chemical Crystallography

, Volume 44, Issue 4, pp 194–204 | Cite as

Synthesis and Structural Analysis of Novel Neuroprotective Pentacyclo[,6.03,10.05,9]undecane- and Adamantane-Derived Propargylamines

  • Jacques Joubert
  • Halima Samsodien
  • Quinton R. Baber
  • Dyanne L. Cruickshank
  • Mino R. Caira
  • Sarel F. Malan
Original Paper


In this article we present a detailed structural investigation of novel polycyclic pentacyclo[,6.03,10.05,9]undecane and adamantane propargylamine hybrid molecules. The structural characterization of these compounds was performed using MS, FT-IR and NMR spectroscopy in combination with X-ray diffraction analysis. The single crystal X-ray analyses of four synthons (6, 810) are presented; 8-(N)-propargylamino-8,11-oxapentacyclo-[,6.03,10.05.9]undecane (compound 6 crystallized in the monoclinic system, unit cell parameters: a = 20.737(2) Å; b = 8.127(1) Å; c = 12.606 (1) Å; β = 92.360(2)°; V = 2122.8(3) Å3; Z = 8); 11-hydroxy-(N)-propargyl-8,11-azapentacyclo[,6.03,10.05.9]undecane (compound 8 crystallized in the monoclinic system, unit cell parameters: a = 7.9624(6) Å; b = 14.9332(6) Å; c = 9.6162(7) Å; β = 109.029(3); V = 1080.9(2) Å3; Z = 4); 1-methyl-11-hydroxy-(N)-propargyl-8,11-azapentacyclo[,6.03,10.05.9]undecane (compound 9 crystallized in the monoclinic system, unit cell parameters: a = 7.732(1) Å; b = 15.148(2) Å; c = 9.864(1) Å; β = 101.728(3)°; V = 1131.3 (2) Å3; Z = 4); and an adamantane derivative, N,N-dipropargyl-adamantan-1-amine (compound 10 crystallized in the orthorhombic system, unit cell parameters: a = 34.098(4) Å; b = 6.825(1) Å; c = 10.979(1) Å; V = 2555.0(5) Å3; Z = 8). From the X-ray analyses it is clear that the polycyclic structures had different modes of intermolecular interaction and molecular stacking. Compound 9 exhibited a cis configuration between the OH and CH3 moieties as expected in view of potential steric hindrance and the electron density effects of the methyl moiety on the initial amination reaction. These hybrid molecules exhibited significant anti-apoptotic activity and could thus find application as neuroprotective agents.

Graphical abstract

A series of pentacyclo[,6.03,10.05,9]undecane- and adamantane-propargylamines were synthesized and characterized by high-resolution MS, FT-IR, 1H-NMR and 13C-NMR spectroscopy and single-crystal X-ray diffraction. These compounds showed promising neuroprotective ability.


X-ray crystal structures NMR Pentacycloundecane Adamantane Propargylamine Neuroprotection 



J. J., H. S., Q. R. B. and S. F. M. would like to thank the South African National Research Foundation (NRF, Pretoria) and the South African Medical Research Council (MRC) for funding. M. R. C. thanks the University of Cape Town and the NRF (Pretoria) for research support. D. L. C. is grateful for receipt of a Claude Leon Foundation Postdoctoral Fellowship.


  1. 1.
    Joubert J, Geldenhuys WJ, Van der Schyf CJ, Oliver DW, Kruger HG, Govender T, Malan SF (2012) Polycyclic cage structures as lipophilic scaffolds for neuro-active drugs. ChemMedChem 7(3):375CrossRefGoogle Scholar
  2. 2.
    Geldenhuys WJ, Malan SF, Bloomquist JR, Marchand AP, Van der Schyf CJ (2005) Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives. Med Res Rev 25(1):21CrossRefGoogle Scholar
  3. 3.
    Davies WL, Grunert RR, Haff RF, McGahen JW, Neumayer EM, Paulshock M, Watts JC, Wood TR, Hermann EC, Hoffmann CE (1964) Antiviral activity of 1-adamantanamine (amantadine). Science 144:862CrossRefGoogle Scholar
  4. 4.
    Schwab RS, Poskanzer DC, England AC, Young RR (1972) Amantadine in Parkinson’s disease. Review of more than two years’ experience. J Am Med Assoc 222(7):792CrossRefGoogle Scholar
  5. 5.
    Mizoguci K, Yokoo H, Yoshida M, Tanaka T, Tanake M (1994) Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-d-aspartate antagonism. Brain Res 662(1–2):255CrossRefGoogle Scholar
  6. 6.
    Danysz W, Parsons CG, Kornhuber J, Schmidt WJ, Quack G (1997) Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents: preclinical studies. Neurosci Biobehav Rev 21(4):455CrossRefGoogle Scholar
  7. 7.
    Oliver DW, Dekker TG, Snyckers FO (1991) Pentacycloundecylamines: synthesis and pharmacology. Eur J Med Chem 26:375CrossRefGoogle Scholar
  8. 8.
    Marchand AP, Arney BE, Dave PR, Satyanarayanan N, Watson WH, Nagl A (1988) Transannular cyclizations in the pentacyclo[,6.03,10.05,9]undecane-8,11-dione system. A reinvestigation. J Org Chem 53(11):2644CrossRefGoogle Scholar
  9. 9.
    Cooksen RC, Grundwell E, Hudec J (1958) Synthesis of cage-like molecules by irradiation of Diels–Alder adducts. Chem Ind 39:1003Google Scholar
  10. 10.
    Geldenhuys WJ, Terre’Blanche G, Van der Schyf CJ, Malan SF (2003) Screening of novel pentacycloundecylamines for neuroprotective activity. Eur J Pharmacol 458:73CrossRefGoogle Scholar
  11. 11.
    Liebenberg W, Van der Watt JJ, Van der Schyf CJ (2000) Effects of derivatives of NGP1-01, a putative calcium channel antagonist, on electrically stimulated guinea-pig papillary muscle. Pharmazie 55(11):833Google Scholar
  12. 12.
    Van der Schyf CJ, Squier GJ, Coetzee WA (1986) Characterization of NGP1-01, an aromatic polycyclic amine, as a calcium antagonist. Pharmacol Res Commun 18(5):407CrossRefGoogle Scholar
  13. 13.
    Malan SF, Van der Walt JJ, Van der Schyf CJ (2000) Structure–activity relationships of polycyclic aromatic amines with calcium channel blocking activity. Pharmazie 333(1):10CrossRefGoogle Scholar
  14. 14.
    Joubert J, Van Dyk S, Green IR, MALAN SF (2011) Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents. Bioorg Med Chem 19:3935CrossRefGoogle Scholar
  15. 15.
    Joubert J, Van Dyk S, Green IR, Malan SF (2011) Synthesis, evaluation and application of polycyclic fluorescent analogues as N-methyl-d-aspartate receptor and voltage gated calcium channel ligands. Eur J Med Chem 46:5010CrossRefGoogle Scholar
  16. 16.
    Geldenhuys WJ, Malan SF, Murugesan T, Van der Schyf CJ, Bloomquist JR (2004) Synthesis and biological evaluation of pentacyclo[,6).0(3,10).0 (5,9)]undecane derivatives as potential therapeutic agents in Parkinson’s disease. Bioorg Med Chem 12:1799CrossRefGoogle Scholar
  17. 17.
    Joubert J, Van Dyk S, Malan SF (2008) Fluorescent polycyclic ligands for nitric oxide synthase (NOS) inhibition. Bioorg Med Chem 16:8952CrossRefGoogle Scholar
  18. 18.
    Liu X, Nuwayhid S, Christie MJ, Kassiou M, Werling LL (2001) Trishomocubanes: novel sigma-receptor ligands modulate amphetamine-stimulated [3H]dopamine release. Eur J Pharmacol 422(1–3):39CrossRefGoogle Scholar
  19. 19.
    Nguyen VH, Kassiou M, Johnson GA, Christie MJ (1996) Comparison of binding parameters of sigma 1 and sigma 2 binding sites in rat and guinea pig brain membranes: novel subtype-selective trishomocubanes. Eur J Pharm 311(2–3):233CrossRefGoogle Scholar
  20. 20.
    Kassiou M, Nguyen VH, Knott R, Christie M, Hambley TW (1996) Trishomocubanes, a new class of selective and high affinity ligands for the sigma binding site. Bioorg Med Chem Lett 6:595CrossRefGoogle Scholar
  21. 21.
    Chen JJ, Swope DM, Dashtipour K (2007) Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin Ther 9:1825CrossRefGoogle Scholar
  22. 22.
    Bar-Am O, Weinreb O, Amit T, Youdim MBH (2005) Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J 19:1899Google Scholar
  23. 23.
    Yu PH, Davis BA, Boulton AA (1992) Aliphatic propargylamines: potent, selective, irreversible monoamine oxidase B inhibitors. J Med Chem 35:3705CrossRefGoogle Scholar
  24. 24.
    Mandel S, Weinreb O, Amit T, Youdim MBH (2005) Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. Brain Res Rev 48:379CrossRefGoogle Scholar
  25. 25.
    Cookson RC, Crundwell E, Hill RR, Hudec J (1964) Photochemical cyclisation of Diels–Alder adducts. J Chem Soc 3062–3075Google Scholar
  26. 26.
    Marchand AP, SuriI SC, Earlywine AD, Powell DR, Van der Helm D (1984) Synthesis of methyl- and nitro-substituted pentacyclo[,6.03,10.05,9]undecane-8,11-diones. J Org Chem 49:670CrossRefGoogle Scholar
  27. 27.
    Program SAINT (2006) Version 7.60a. Bruker AXS Inc., MadisonGoogle Scholar
  28. 28.
    Otwinowski Z, Minor W (2000) In: Rossman MG, Arnold E (eds) International tables for crystallography, vol. F. Kluwer, DordrechtGoogle Scholar
  29. 29.
    XPREP2, Bruker (2008) Version 2008/2 for Windows. Bruker AXS Inc., MadisonGoogle Scholar
  30. 30.
    Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr A 64:112CrossRefGoogle Scholar
  31. 31.
    POV-Ray for Windows (2004) Version 3.6. Persistence of vision raytracerGoogle Scholar
  32. 32.
    Spek AL (2003) Single-crystal structure validation with the program PLATON. J Appl Crystallogr 36:7CrossRefGoogle Scholar
  33. 33.
    Paquette LA, Nakamura K, Engel P (1986) Synthesis of hexacyclo [,6.03,10.04,8.09,12]dodecane-5,11-dione and its conversion to di-, tri, and teranitro-1,3-bishomopentaprismanes. Chem Ber 119:3782CrossRefGoogle Scholar
  34. 34.
    Ammon HL, Du Z (1988) Structure of the quasi-equatorial isomer of 5,11-dinitrohexacyclo[,6.03,10.04,8.09,12]dodecane and crystal density calculations for several di-, tri and tetranitro analogs. Acta Cryst Sect C 44:1059Google Scholar
  35. 35.
    Ammon HL, Paquette LA (1991) Structure of 1,5,9-trinitrobishomopentaprismane. Acta Cryst Sect C 47:2159CrossRefGoogle Scholar
  36. 36.
    Cambridge Structural Database and Cambridge Structural Database System (2012) Version 5.33. Cambridge Crystallographic Data Centre, University Chemical Laboratory, CambridgeGoogle Scholar
  37. 37.
    ArgusLab (2004) Version 4.0.1. Mark Thompson and Planaria Software LLC, SeattleGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jacques Joubert
    • 1
  • Halima Samsodien
    • 1
  • Quinton R. Baber
    • 2
  • Dyanne L. Cruickshank
    • 3
  • Mino R. Caira
    • 3
  • Sarel F. Malan
    • 1
  1. 1.School of PharmacyUniversity of the Western CapeBellvilleSouth Africa
  2. 2.Pharmaceutical ChemistryNorth-West UniversityPotchefstroomSouth Africa
  3. 3.Department of ChemistryUniversity of Cape TownRondeboschSouth Africa

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