Skip to main content
SpringerLink
Log in

Synthesis and Structural Analysis of Novel Neuroprotective Pentacyclo[5.4.1.02,6.03,10.05,9]undecane- and Adamantane-Derived Propargylamines

  • Original Paper
  • Published:
Journal of Chemical Crystallography Aims and scope Submit manuscript

Abstract

In this article we present a detailed structural investigation of novel polycyclic pentacyclo[5.4.1.02,6.03,10.05,9]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, 8–10) are presented; 8-(N)-propargylamino-8,11-oxapentacyclo-[5.4.1.02,6.03,10.05.9]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[5.4.1.02,6.03,10.05.9]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[5.4.1.02,6.03,10.05.9]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[5.4.1.02,6.03,10.05,9]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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Scheme 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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):375

    Article  CAS  Google Scholar 

  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):21

    Article  CAS  Google Scholar 

  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 144:862

    Article  CAS  Google Scholar 

  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):792

    Article  CAS  Google Scholar 

  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):255

    Article  Google Scholar 

  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):455

    Article  CAS  Google Scholar 

  7. Oliver DW, Dekker TG, Snyckers FO (1991) Pentacycloundecylamines: synthesis and pharmacology. Eur J Med Chem 26:375

    Article  CAS  Google Scholar 

  8. Marchand AP, Arney BE, Dave PR, Satyanarayanan N, Watson WH, Nagl A (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(11):2644

    Article  CAS  Google Scholar 

  9. Cooksen RC, Grundwell E, Hudec J (1958) Synthesis of cage-like molecules by irradiation of Diels–Alder adducts. Chem Ind 39:1003

    Google Scholar 

  10. Geldenhuys WJ, Terre’Blanche G, Van der Schyf CJ, Malan SF (2003) Screening of novel pentacycloundecylamines for neuroprotective activity. Eur J Pharmacol 458:73

    Article  CAS  Google Scholar 

  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):833

    CAS  Google Scholar 

  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):407

    Article  Google Scholar 

  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):10

    Article  CAS  Google Scholar 

  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 19:3935

    Article  CAS  Google Scholar 

  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 46:5010

    Article  CAS  Google Scholar 

  16. Geldenhuys WJ, Malan SF, Murugesan T, Van der Schyf CJ, Bloomquist JR (2004) Synthesis and biological evaluation of pentacyclo[5.4.0.0(2,6).0(3,10).0 (5,9)]undecane derivatives as potential therapeutic agents in Parkinson’s disease. Bioorg Med Chem 12:1799

    Article  CAS  Google Scholar 

  17. Joubert J, Van Dyk S, Malan SF (2008) Fluorescent polycyclic ligands for nitric oxide synthase (NOS) inhibition. Bioorg Med Chem 16:8952

    Article  CAS  Google Scholar 

  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):39

    Article  CAS  Google Scholar 

  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):233

    Article  CAS  Google Scholar 

  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 6:595

    Article  CAS  Google Scholar 

  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 9:1825

    Article  CAS  Google Scholar 

  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 19:1899

    CAS  Google Scholar 

  23. Yu PH, Davis BA, Boulton AA (1992) Aliphatic propargylamines: potent, selective, irreversible monoamine oxidase B inhibitors. J Med Chem 35:3705

    Article  CAS  Google Scholar 

  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 48:379

    Article  CAS  Google Scholar 

  25. Cookson RC, Crundwell E, Hill RR, Hudec J (1964) Photochemical cyclisation of Diels–Alder adducts. J Chem Soc 3062–3075

  26. Marchand AP, SuriI SC, Earlywine AD, Powell DR, Van der Helm D (1984) Synthesis of methyl- and nitro-substituted pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-diones. J Org Chem 49:670

    Article  CAS  Google Scholar 

  27. Program SAINT (2006) Version 7.60a. Bruker AXS Inc., Madison

  28. Otwinowski Z, Minor W (2000) In: Rossman MG, Arnold E (eds) International tables for crystallography, vol. F. Kluwer, Dordrecht

    Google Scholar 

  29. XPREP2, Bruker (2008) Version 2008/2 for Windows. Bruker AXS Inc., Madison

  30. Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr A 64:112

    Article  CAS  Google Scholar 

  31. POV-Ray for Windows (2004) Version 3.6. Persistence of vision raytracer

  32. Spek AL (2003) Single-crystal structure validation with the program PLATON. J Appl Crystallogr 36:7

    Article  CAS  Google Scholar 

  33. Paquette LA, Nakamura K, Engel P (1986) Synthesis of hexacyclo [5.4.1.02,6.03,10.04,8.09,12]dodecane-5,11-dione and its conversion to di-, tri, and teranitro-1,3-bishomopentaprismanes. Chem Ber 119:3782

    Article  CAS  Google Scholar 

  34. Ammon HL, Du Z (1988) Structure of the quasi-equatorial isomer of 5,11-dinitrohexacyclo[5.4.1.02,6.03,10.04,8.09,12]dodecane and crystal density calculations for several di-, tri and tetranitro analogs. Acta Cryst Sect C 44:1059

    Google Scholar 

  35. Ammon HL, Paquette LA (1991) Structure of 1,5,9-trinitrobishomopentaprismane. Acta Cryst Sect C 47:2159

    Article  Google Scholar 

  36. Cambridge Structural Database and Cambridge Structural Database System (2012) Version 5.33. Cambridge Crystallographic Data Centre, University Chemical Laboratory, Cambridge

  37. ArgusLab (2004) Version 4.0.1. Mark Thompson and Planaria Software LLC, Seattle

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, 7535, South Africa

    Jacques Joubert, Halima Samsodien & Sarel F. Malan

  2. Pharmaceutical Chemistry, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa

    Quinton R. Baber

  3. Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa

    Dyanne L. Cruickshank & Mino R. Caira

Authors
  1. Jacques Joubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Halima Samsodien
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Quinton R. Baber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dyanne L. Cruickshank
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mino R. Caira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sarel F. Malan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sarel F. Malan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Joubert, J., Samsodien, H., Baber, Q.R. et al. Synthesis and Structural Analysis of Novel Neuroprotective Pentacyclo[5.4.1.02,6.03,10.05,9]undecane- and Adamantane-Derived Propargylamines. J Chem Crystallogr 44, 194–204 (2014). https://doi.org/10.1007/s10870-014-0501-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10870-014-0501-y

Keywords

Search

Navigation