Planta Med 2015; 81(12/13): 1163-1168
DOI: 10.1055/s-0035-1546106
Natural Product Chemistry
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Cytotoxic Amides from Fruits of Kawakawa, Macropiper excelsum [*]

Jeremy Lei
1   Department of Chemistry, University of Otago, Dunedin, New Zealand
,
Elaine J. Burgess
2   The New Zealand Institute for Plant & Food Research Limited, Department of Chemistry, University of Otago, Dunedin, New Zealand
,
Alistair T. B. Richardson
1   Department of Chemistry, University of Otago, Dunedin, New Zealand
,
Bill C. Hawkins
1   Department of Chemistry, University of Otago, Dunedin, New Zealand
,
Sarah K. Baird
3   Department of Pharmacology & Toxicology, University of Otago, Dunedin, New Zealand
,
Bruce M. Smallfield
2   The New Zealand Institute for Plant & Food Research Limited, Department of Chemistry, University of Otago, Dunedin, New Zealand
,
John W. van Klink
2   The New Zealand Institute for Plant & Food Research Limited, Department of Chemistry, University of Otago, Dunedin, New Zealand
,
Nigel B. Perry
1   Department of Chemistry, University of Otago, Dunedin, New Zealand
2   The New Zealand Institute for Plant & Food Research Limited, Department of Chemistry, University of Otago, Dunedin, New Zealand
› Author Affiliations
Further Information

Publication History

received 12 March 2015
revised 14 April 2015

accepted 19 April 2015

Publication Date:
03 June 2015 (online)

Abstract

Cytotoxic amides have been isolated from the fruits of the endemic New Zealand medicinal plant kawakawa, Macropiper excelsum (Piperaceae). The main amide was piperchabamide A and this is the first report of this rare compound outside the genus Piper. Eleven other amides were purified including two new compounds with the unusual 3,4-dihydro-1(2H)-pyridinyl group. The new compounds were fully characterized by 2D NMR spectroscopy, which showed a slow exchange between two rotamers about the amide bond, and they were chemically synthesized. In view of the antitumor activity of the related piperlongumine, all of these amides plus four synthetic analogs were tested for cytotoxicity. The most active was the piperine homolog piperdardine, with an IC50 of 14 µM against HT 29 colon cancer cells.

* Dedicated to Professor Dr. Dr. h. c. mult. Adolf Nahrstedt on the occasion of his 75th birthday.


Supporting Information

 
  • References

  • 1 Wardle P. Vegetation of New Zealand. Cambridge: Cambridge University Press; 1991
  • 2 Riley M. Maori healing and herbal. Paraparaumu: Viking Sevenseas N.Z. Ltd.; 1994
  • 3 Smith AC. The genus Macropiper (Piperaceae). Bot J Linn Soc 1975; 71: 1-38
  • 4 Anonymous Ngā Tipu o Aotearoa – New Zealand Plant Names Database. Available at http://nzflora.landcareresearch.co.nz/ Accessed January 27, 2015
  • 5 Anonymous Ngā Tipu Whakaoranga – Māori Plant Use Database. Available at http://maoriplantuse.landcareresearch.co.nz Accessed January 27, 2015
  • 6 Calder VL, Cole ALJ, Walker JRL. Antibiotic compounds from New Zealand plants. III: A survey of some New Zealand plants for antibiotic substances. J Royal Soc N Z 1986; 16: 169-181
  • 7 Lechtenberg M, Quandt B, Schmidt M, Nahrstedt A. Is the alkaloid pipermethystine connected with the claimed liver toxicity of Kava products?. Pharmazie 2008; 63: 71-74
  • 8 Schmidt M, Nahrstedt A, Lupke NP. [Piper methysticum (kava) under discussion: observations on quality, effectiveness and safety]. Wien Med Wochenschr 2002; 152: 382-388
  • 9 Lechtenberg M, Quandt B, Kohlenberg FJ, Nahrstedt A. Qualitative and quantitative micellar electrokinetic chromatography of kavalactones from dry extracts of Piper methysticum Forst. and commercial drugs. J Chromatogr A 1999; 848: 457-464
  • 10 Briggs LH. The essential oil of Macropiper excelsum . J Soc Chem Ind 1941; 60: 210-212
  • 11 Briggs LH, Kingsford M, Leonard JH, White GW. New Zealand phytochemical survey. 12. The essential oils of some New Zealand species. N Z J Sci 1975; 18: 549-554
  • 12 Briggs LH, Cambie RC, Crouch RAF. Lirioresinol-C dimethyl ether, a diaxially substituted 3,7-dioxabicyclo[3.3.0]octane lignan from Macropiper excelsum . J Chem Soc C 1968; 3042-3045
  • 13 Russell GB, Fenemore PG. New lignans from leaves of Macropiper excelsum . Phytochemistry 1973; 12: 1799-1803
  • 14 De Leon EJ, Olmedo DA, Solis PN, Gupta MP, Terencio MC. Diayangambin exerts immunosuppressive and anti-inflammatory effects in vitro and in vivo . Planta Med 2002; 68: 1128-1131
  • 15 Okwute SK, Egharevba HO. Piperine-type amides. Review of the chemical and biological characteristics. Int J Chem 2013; 5: 99-122
  • 16 Meghwal M, Goswami TK. Piper nigrum and piperine: an update. Phytother Res 2013; 27: 1121-1130
  • 17 Gutierrez RMP, Gonzalez AMN, Hoyo-Vadillo C. Alkaloids from Piper: a review of its phytochemistry and pharmacology. Mini-Rev Med Chem 2013; 13: 163-193
  • 18 Bezerra DP, Ferreira PMP, Machado CML, de Aquino NC, Silveira ER, Chammas R, Pessoa C. Antitumour efficacy of Piper tuberculatum and piplartine based on the hollow fiber assay. Planta Med 2015; 81: 15-19
  • 19 Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 2011; 475: 231-234
  • 20 Allan HH. Flora of New Zealand. Indigenous Tracheophyta, Psilopsida, Lycopsida, Filicopsida, Gymnospermae, Dicotyledones. Wellington: DSIR; 1961
  • 21 Burrows CJ. Germination Behavior of the Seeds of 6 New Zealand Woody Plant Species. N Z J Bot 1995; 33: 365-377
  • 22 Dawson J, Lucas R. New Zealandʼs native trees. Nelson: Craig Potton; 2011
  • 23 Morikawa T, Matsuda H, Yamaguchi I, Pongpiriyadacha Y, Yoshikawa M. New amides and gastroprotective constituents from the fruit of Piper chaba . Planta Med 2004; 70: 152-159
  • 24 Kaou AM, Mahiou-Leddet V, Canlet C, Debrauwer L, Hutter S, Azas N, Ollivier E. New amide alkaloid from the aerial part of Piper capense L.f. (Piperaceae). Fitoterapia 2010; 81: 632-635
  • 25 do Nascimento JC, De Paula VF, David JM, David JP. Occurrence, biological activities and 13C NMR data of amides from Piper (Piperaceae). Quim Nova 2012; 35: 2288-2311
  • 26 Davis DG, Bax A. Separation of chemical exchange and cross-relaxation effects in two-dimensional NMR spectroscopy. J Magn Reson 1985; 64: 533-535
  • 27 Ferrie L, Bouzbouz S, Cossy J. Acryloyl chloride: an excellent substrate for cross-metathesis. A one-pot sequence for the synthesis of substituted alpha,beta-unsaturated carbonyl derivatives. Org Lett 2009; 11: 5446-5448
  • 28 Hofer O, Greger H, Robien W, Werner A. 13C NMR and 1H lanthanide induced shifts of naturally occurring alkamides with cyclic amide moieties – amides from Achillea falcata . Tetrahedron 1986; 42: 2707-2716
  • 29 Patil AD, Freyer AJ, Reichwein R, Hofmann G, Johnson RK. Piperpense, a tetrahydropyridine alkaloid from Piper ponapense stems and leaves. Nat Prod Lett 1997; 9: 217-223
  • 30 Cruz-Cabeza AJ, Bernstein J. Conformational polymorphism. Chem Rev 2014; 114: 2170-2191
  • 31 Perry NB, Blunt JW, Munro MHG. Different solution and solid-state conformations of the antibiotic cycloheximide. Magn Reson Chem 1989; 27: 624-627
  • 32 Kuropka G, Glombitza KW. Further polyenic and polyynic carboxamides and sesamin from Achillea ptarmica . Planta Med 1987; 53: 440-442
  • 33 Curran DP, Yoon MH. Can an aromatic ring alter the reactions of a nearby unsaturated imide? A study of the rate and selectivity of nitrile oxide cycloaddition reactions of acryloyl derivatives of the Rebek imide benzoxazole. Tetrahedron 1997; 53: 1971-1982
  • 34 Barker G, McGrath JL, Klapars A, Stead D, Zhou G, Campos KR, OʼBrien P. Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: in situ react IR spectroscopic monitoring, scope, and synthetic applications. J Org Chem 2011; 76: 5936-5953
  • 35 Adesina SK, Reisch J. Amides from Zanthoxylum rubescens . Phytochemistry 1989; 28: 839-842
  • 36 Chen JJ, Huang YC, Chen YC, Huang YT, Wang SW, Peng CY, Teng CM, Chen IS. Cytotoxic amides from Piper sintenense . Planta Med 2002; 68: 980-985
  • 37 Matsuda H, Ninomiya K, Morikawa T, Yasuda D, Yamaguchi I, Yoshikawa M. Protective effects of amide constituents from the fruit of Piper chaba on D-galactosamine/TNF-alpha-induced cell death in mouse hepatocytes. Bioorg Med Chem Lett 2008; 18: 2038-2042
  • 38 Adams DJ, Dai M, Pellegrino G, Wagner BK, Stern AM, Shamji AF, Schreiber SL. Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs. Proc Natl Acad Sci U S A 2012; 109: 15115-15120
  • 39 Weidner-Wells MA, Fraga-Spano SA, Turchi IJ. Unusual regioselectivity of the dipolar cycloaddition reactions of nitrile oxides and tertiary cinnamides and crotonamides. J Org Chem 1998; 63: 6319-6328
  • 40 Sekiya T, Hiranuma H, Hats S, Mizogami S, Hanazuka M, Yamada S. Pyrimidine derivatives. 4. Synthesis and antihypertensive activity of 4-amino-2-(4-cinnamoylpiperazino)-6,7-dimethoxyquinazoline derivatives. J Med Chem 1983; 26: 411-441
  • 41 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
  • 42 Pedersen ME, Metzler B, Stafford GI, van Staden J, Jager AK, Rasmussen HB. Amides from Piper capense with CNS activity – a preliminary SAR analysis. Molecules 2009; 14: 3833-3843
  • 43 De Araujo-Junior JX, Da-Cunha EVL, Chaves MCO, Gray AI. Piperdardine, a piperidine alkaloid from Piper tuberculatum . Phytochemistry 1997; 44: 559-561
  • 44 Bernard CB, Krishnamurty HG, Chauret D, Durst T, Philogene BJR, Sanchez-Vindas P, Hasbun C, Poveda L, San Roman L, Arnason JT. Insecticidal defenses of Piperaceae from the neotropics. J Chem Ecol 1995; 21: 801-814
  • 45 Ding Z, Ding J, Chen Z, Bai P, Nanao H, Hisashi K. Amides from Asarum chingchengense . Phytochemistry 1991; 30: 3797-3798
  • 46 Cheng MJ, Yang CH, Lin WY, Lin WY, Tsai IL, Chen IS. Chemical constituents from the leaves of Zanthoxylum schinifolium . J Chin Chem Soc 2002; 49: 125-128
  • 47 Correa EA, Hogestatt ED, Sterner O, Echeverri F, Zygmunt PM. In vitro TRPV1 activity of piperine derived amides. Bioorg Med Chem 2010; 18: 3299-3306