Download PDF
Planta Med 2006; 72(2): 162-168
DOI: 10.1055/s-2005-873196
Original Paper
Natural Product Chemistry
© Georg Thieme Verlag KG Stuttgart · New York

New Macrocyclic Lathyrane Diterpenes, from Euphorbia lagascae, as Inhibitors of Multidrug Resistance of Tumour Cells

Noélia Duarte1 , Nora Gyémánt2 , Pedro M. Abreu3 , Joseph Molnár2 , Maria-José U. Ferreira1
  • 1CECF, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
  • 2Department of Medical Microbiology, University of Szeged, Szeged, Hungary
  • 3CQFB/REQUIMTE, Faculty of Sciences and Technology, New University of Lisbon, Caparica, Portugal
Further Information

Publication History

Received: May 20, 2005

Accepted: June 20, 2005

Publication Date:
05 December 2005 (online)

Also available at
    Permissions and Reprints

Abstract

The new macrocyclic lathyrane diterpenes latilagascenes A and B (1 and 2), the diacetylated derivative of 2, latilagascene C (3), and the known diterpenes ent-16α,17-dihydroxyatisan-3-one (4) and ent-16α,17-dihydroxykauran-3-one (5), isolated from the methanol extract of Euphorbia lagascae, were examined for their effects on the reversal of multidrug resistance (MDR) on mouse lymphoma cells. Among the active lathyrane derivatives 1 - 3, compound 2 displayed the highest inhibition of rhodamine 123 efflux of human MDR1 gene transfected mouse lymphoma cells when compared to the untreated cells or the positive control verapamil. The new compounds are the first macrocyclic lathyrane diterpenes showing oxidation at C-16, whose structures were characterized by extensive spectroscopic methods, including 2D NMR experiments (1H-1H COSY, HMQC, HMBC and NOESY). The known phenolic compounds vanillic acid (6), p-salicylic acid (7), isofraxidin (8) and cleomiscosin A (9) were also isolated from this species.

Key words

Euphorbia lagascae - lathyrane - diterpenes - phenolic compounds - multidrug resistance - P-glycoprotein

References

  • 1 Grossi A, Biscardi M. Reversal of MDR by verapamil analogues.  Hematology. 2004;  9 47-56
    CrossrefPubMedSearch in Google Scholar
  • 2 Gottesman M M, Fojo T, Bates S E. Multidrug resistance in cancer: role of ATP-dependent transporters.  Nat Rev Cancer. 2002;  2 48-58
    CrossrefPubMedSearch in Google Scholar
  • 3 Teodori E, Dei S, Scapecchi S, Gualtieri F. The medicinal chemistry of multidrug resistance (MDR) reversing Drugs.  Il Farmaco. 2002;  57 385-415
    CrossrefPubMedSearch in Google Scholar
  • 4 Cahoon E B, Ripp K G, Hall S E, McGonigle B. Transgenic production of epoxy fatty acids by expression of a cytochrome P450 enzyme from Euphorbia lagascae seed.  Plant Physiol. 2002;  128 615-24
    CrossrefPubMedSearch in Google Scholar
  • 5 Ferrigni N R., McLaughlin J L, Powell R G, Smith C R. Use of potato disc and brine shrimp bioassays to detect activity and isolate piceatannol as the antileukemic principle from the seeds of Euphorbia lagascae .  J Nat Prod. 1984;  47 347-52
    CrossrefPubMedSearch in Google Scholar
  • 6 Valente C, Ferreira M JU, Abreu P M, Gyémánt N, Ugocsai K, Hohmann J. et al . Pubescenes, jatrophane diterpenes, from Euphorbia pubescens with multidrug resistance reversing activity on mouse lymphoma cells.  Planta Med. 2004;  70 81-4
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Hohmann J, Molnár J, Rédei D, Evanics F, Forgó P, Kálmán A. et al . Discovery and biological evaluation of a new family of potent modulators of multidrug resistance: reversal of MDR of mouse lymphoma cells by new natural jatrophane diterpenoids isolated from Euphorbia species.  J Med Chem. 2002;  45 2425-31
    CrossrefPubMedSearch in Google Scholar
  • 8 Corea G, Fattorusso E, Lanzotti V, Motti R, Simon P N, Dumontet C. et al . Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A.  J Med Chem. 2004;  47 988-92
    CrossrefPubMedSearch in Google Scholar
  • 9 Appendino G, Della Porta C, Conseil G, Sterner O, Mercalli E, Dumontet C. et al . A new P-glycoprotein inhibitor from the caper spurge (Euphorbia lathyris).  J Nat Prod. 2003;  66 140-2
    CrossrefPubMedSearch in Google Scholar
  • 10 Coenwell M M, Pastan I, Gottesmann M M. Certain calcium channel blockers bind specifically to multidrug-resistance human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein.  J Biol Chem. 1987;  262 2166-70
    PubMedSearch in Google Scholar
  • 11 Weaver J L, Szabo G, Pine P S, Gottesman M M, Goldenberg S, Aszalos A. The effect of ion channel blockers, immunosuppressive agents, and other drugs on the activity of the multidrug transporter.  Int J Cancer. 1993;  54 456-61
    PubMedSearch in Google Scholar
  • 12 Kessel D. Exploring multidrug resistance using rhodamine 123. Cancer Commun 1989: 145-9
    Search in Google Scholar
  • 13 Lieu L G, Tan R X. New jatrophane diterpenoid esters from Euphorbia turczaninowii .  J Nat Prod. 2001;  64 1064-8 and related references cited therein
    CrossrefPubMedSearch in Google Scholar
  • 14 Uemura D, Nakayama Y, Shizuri Y, Hirata Y. The structure of new lathyrane diterpenes, Jolkinols A, B, C and D from Euphorbia jolkini Boiss. Tetrahedron Lett 1976: 4593-6
    Search in Google Scholar
  • 15 Seip E, Hecker E. Lathyrane type diterpenoid esters from Euphorbia characias .  Phytochemistry. 1983;  22 1791-5
    CrossrefPubMedSearch in Google Scholar
  • 16 Vasas A, Hohmann J, Forgo P, Szabo P. New tri- and tetracyclic diterpenes from Euphorbia villosa .  Tetrahedron. 2004;  60 5025-30
    CrossrefPubMedSearch in Google Scholar
  • 17 Lal A, Cambie R, Rutledge P, Woodgate P. Ent-atisane diterpenes from Euphorbia fidjiana .  Phytochemistry. 1990;  29 1925-35
    CrossrefPubMedSearch in Google Scholar
  • 18 Gustafson K, Munro M, Blunt J. HIV inhibitory natural products. 3. Diterpenes from Homalanthus acuminatus and Chrysobalanus icaco .  Tetrahedron. 1991;  47 4547-54
    CrossrefPubMedSearch in Google Scholar
  • 19 Huang Z, Dostal L, Rosazza J. Mechanisms of ferulic acid conversions to vanillic and guaiacol by Rhodotorula ombra .  J Biol Chem. 1993;  268 23 954-8
    PubMedSearch in Google Scholar
  • 20 Tan J, Bednarek P, Liu J, Schneider B, Svatôs A, Hahlbrock K. Universally occurring phenylpropanoid and species-specific indolic metabolites in infected and uninfected Arabidopsis thaliana roots and leaves.  Phytochemistry. 2004;  65 691-9
    CrossrefPubMedSearch in Google Scholar
  • 21 Panichayupakaranant P, Noguchi H, De-Eknamkul W, Sankawa U. Naphthoquinones and coumarins from Impatiens Balsamina root cultures.  Phytochemistry. 1995;  40 1141-3
    CrossrefPubMedSearch in Google Scholar
  • 22 Ray A, Chattopadhyay S, Kumar S, Konno C, Kiso Y, Hikino H. Structure of cleomiscosins, coumarinolignoids of Cleome viscosa seeds.  Tetrahedron. 1985;  41 209-14
    CrossrefPubMedSearch in Google Scholar
  • 23 Klopman G, Shi L M, Ramu A. Quantitative structure-activity relationship of multidrug resistance reversal agents.  Mol Pharmacol. 1997;  52 323-34
    PubMedSearch in Google Scholar
  • 24 Seelig A, Landwojtowicz E. Structure-activity relationship of P-glycoprotein substrates and modifiers.  Eur J Pharm Sci. 2000;  12 31-40
    PubMedSearch in Google Scholar
  • 25 Corea G, Fattorusso E, Lanzotti V, Taglialatela-Scafati O, Appendino G, Ballero M. et al . Modified jatrophane diterpenes as modulators of multidrug resistance from Euphorbia dendroides .  Bioorg Med Chem. 2003;  11 5221-7
    PubMedSearch in Google Scholar
  • 26 Corea G, Fattorusso E, Lanzotti V, Motti R, Simon P N, Dumontet C. et al . Structure-activity relationships for Euphocharactins A-L, a new series of jatrophane diterpenes, as inhibitors of cancer cell P-glycoprotein.  Planta Med. 2004;  70 657-65
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Corea G, Fattorusso E, Lanzotti V, Taglialatela-Scafati O, Appendino G, Ballero M. et al . Jatrophane diterpenes as P-glycoprotein inhibitors. First insights of structure-activity relationships and discovery of a new, powerful lead.  J Med Chem. 2003;  46 3395-402
    CrossrefPubMedSearch in Google Scholar

Prof. Maria José Umbelino Ferreira

CECF

Faculty of Pharmacy

University of Lisbon

Av. das Forças Armadas

1600-083 Lisbon

Portugal

Fax: +351-21-794-6470

Email: mjuferreira@ff.ul.pt