Download PDF
Planta Med 2018; 84(09/10): 729-735
DOI: 10.1055/a-0589-0525
Natural Product Chemistry and Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Bioactive Segetane, Ingenane, and Jatrophane Diterpenes from Euphorbia taurinensis

Dóra Rédei
1   Department of Pharmacognosy, University of Szeged, Szeged, Hungary
,
Norbert Kúsz
1   Department of Pharmacognosy, University of Szeged, Szeged, Hungary
,
Gréta Sátori
1   Department of Pharmacognosy, University of Szeged, Szeged, Hungary
,
Annamária Kincses
2   Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary
,
Gabriella Spengler
2   Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary
,
Katalin Burián
2   Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary
,
Zoltán Barina
3   Department of Botany, Hungarian Natural History Museum, Budapest, Hungary
,
Judit Hohmann
1   Department of Pharmacognosy, University of Szeged, Szeged, Hungary
4   Interdisciplinary Centre of Natural Products, University of Szeged, Szeged, Hungary
› Author Affiliations
Further Information

Publication History

received 12 January 2018
revised 02 March 2018

accepted 06 March 2018

Publication Date:
19 March 2018 (online)

   Permissions and Reprints

Abstract

A novel segetane (1) and jatrophane diterpene (2), together with five known diterpenoids possessing segetane (3), jatrophane (4), and ingenane skeletons (5 – 7), were isolated from the methanol extract of Euphorbia taurinensis All. The structure elucidation of the compounds was performed by means of extensive spectroscopic analysis, including HRESIMS and 1D (1H, J-modulated spin-echo carbon experiment) and 2D (HSQC, HMBC, COSY, NOESY) NMR experiments. The multidrug resistance reversing and cytotoxic effects of five diterpenes (1, 4 – 7) were studied on the L5178 mouse lymphoma cell line using rhodamine 123 accumulation and the MTT cell viability assay. Segetane and jatrophane diterpenes had no cytotoxic activity on the sensitive parent and multidrug resistance cells, while ingenane diterpenes showed a cytotoxic effect on both cell lines. Ingenanes 6 and 7 and segetane 1 demonstrated the remarkable multidrug resistance modulating effect at 20 µM.

Key words

Euphorbia taurinensis - Euphorbiaceae - diterpene - segetane - jatrophane - ingenane - multidrug resistance

Supporting Information

    HRMS and NMR spectra of 1 and 2, flow cytometric charts of 1, 4 – 7, and cytotoxicity dose-response curves of 6 and 7 are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 The Plant List (2013). Version 1.1. Available at. http://www.theplantlist.org/ Accessed January 1, 2018
    PubMedGoogle Scholar
  • 2 Evans FJ, Taylor SE. Pro-inflammatory, tumour-promoting and anti-tumour Diterpenes of the Plant Families Euphorbiaceae and Thymelaeaceae. In: Herz W, Grisebach H, Kirby GW. eds. Progress in the Chemistry of organic natural Products, Vol. 44. Vienna: Springer; 1983: 1-99
    Google Scholar
  • 3 Vasas A, Hohmann J. Euphorbia diterpenes: isolation, structure, biological activity, and synthesis (2008–2012). Chem Rev 2014; 114: 8579-8612
    CrossrefPubMedGoogle Scholar
  • 4 Boyle GM, DʼSouza MMA, Pierce CJ, Adams RA, Cantor AS, Johns JP, Maslovskaya L, Gordon VA, Reddell PW, Parsons PG. Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models. PLoS One 2014; 9: e108887
    CrossrefPubMedGoogle Scholar
  • 5 Williams SA, Chen LF, Kwon H, Fenard D, Bisgrove D, Verdin E, Greene WC. Prostratin antagonizes HIV latency by activating NF-kappaB. J Biol Chem 2004; 279: 42008-42017
    CrossrefPubMedGoogle Scholar
  • 6 Lai W, Huang L, Zhu L, Ferrari G, Chan C, Li W, Lee KH, Chen CH. Gnidimacrin, a potent anti-HIV diterpene, can eliminate latent HIV-1 ex vivo by activation of protein kinase C β . J Med Chem 2015; 58: 8638-8646
    CrossrefPubMedGoogle Scholar
  • 7 Vasas A, Rédei D, Csupor D, Molnár J, Hohmann J. Diterpenes from European Euphorbia species serving as prototypes for natural-product-based drug discovery. Eur J Org Chem 2012; 2012: 5115-5130
    CrossrefPubMedGoogle Scholar
  • 8 Kissin I, Szallasi A. Therapeutic targeting of TRPV1 by resiniferatoxin, from preclinical studies to clinical trials. Curr Top Med Chem 2011; 11: 2159-2170
    CrossrefPubMedGoogle Scholar
  • 9 Resiniferatoxin to treat severe pain associated with advanced cancer. Available at. https://clinicaltrials.gov/show/NCT00804154 Accessed January 1, 2018
    PubMedGoogle Scholar
  • 10 Study to evaluate safety and MTD of epidural resiniferatoxin injection for treatment of intractable cancer pain. Available at. https://clinicaltrials.gov/ct2/show/NCT03226574 Accessed January 1, 2018
    PubMedGoogle Scholar
  • 11 Hohmann J, Molnár J, Rédei D, Evanics F, Forgo P, Kálmán A, Argay G, Szabó P. Discovery and biological evaluation of a new family of potent modulators of multidrug resistance: reversal of multidrug resistance of mouse lymphoma cells by new natural jatrophane diterpenoids isolated from Euphorbia species. J Med Chem 2002; 45: 2425-2431
    CrossrefPubMedGoogle Scholar
  • 12 Lanzotti V, Barile E, Scambia G, Ferlini C. Cyparissins A and B, jatrophane diterpenes from Euphorbia cyparissias as Pgp inhibitors and cytotoxic agents against ovarian cancer cell lines. Fitoterapia 2015; 104: 75-79
    CrossrefPubMedGoogle Scholar
  • 13 Wang HY, Wang JS, Wei DD, Wang XB, Luo J, Yang MH, Kong LY. Bioactivity-guided isolation of antiproliferative diterpenoids from Euphorbia kansui . Phytother Res 2012; 26: 853-859
    CrossrefPubMedGoogle Scholar
  • 14 Mongkolvisut W, Sutthivaiyakit S. Antimalarial and antituberculous poly-O-acylated jatrophane diterpenoids from Pedilanthus tithymaloides . J Nat Prod 2007; 70: 1434-1438
    CrossrefPubMedGoogle Scholar
  • 15 Nothias-Scaglia LF, Retailleau P, Pannecouque C, Neyts J, Dumontet V, Roussi F, Leyssen P, Costa J, Litaudon M. Jatrophane diterpenes as inhibitors of chikungunya virus replication: structure-activity relationship and discovery of a potent lead. J Nat Prod 2014; 77: 1505-1512
    CrossrefPubMedGoogle Scholar
  • 16 Bedoya LM, Márquez N, Martínez N, Guitérrez-Eisman S, Alvarez A, Calzado MA, Rojas JM, Appendino G, Muñoz E, Alcamí J. SJ23B, a jatrophane diterpene activates classical PKCs and displays strong activity against HIV in vitro . Biochem Pharmacol 2009; 77: 965-978
    CrossrefPubMedGoogle Scholar
  • 17 Ferreira RJ, dos Santos DJ, Ferreira MJ, Guedes RC. Toward a better pharmacophore description of P-glycoprotein modulators, based on macrocyclic diterpenes from Euphorbia species. J Chem Inf Model 2011; 51: 1315-1324
    CrossrefPubMedGoogle Scholar
  • 18 Wiśniewski J, Wesołowska O, Środa-Pomianek K, Paprocka M, Bielawska-Pohl A, Krawczenko A, Duarte N, Ferreira MJ, Duś D, Michalak K. Euphorbia species-derived diterpenes and coumarins as multidrug resistance modulators in human colon carcinoma cells. Anticancer Res 2016; 36: 2259-2264
    PubMedGoogle Scholar
  • 19 Reis MA, Ahmed OB, Spengler G, Molnár J, Lage H, Ferreira MJ. Jatrophane diterpenes and cancer multidrug resistance – ABCB1 efflux modulation and selective cell death induction. Phytomedicine 2016; 23: 968-978
    CrossrefPubMedGoogle Scholar
  • 20 Smith AR, Tutin TG. 7. Euphorbia L. In: Tutin TG, Heywood VH, Burges NA, Moore DM, Valentine DH, Walters SM, Webb DA. eds. Flora Europaea, Vol. 2. Cambridge: Cambridge University Press; 1968: 213-226
    Google Scholar
  • 21 Abdelgaleil SA, Kassem SM, Doe M, Baba M, Nakatani M. Diterpenoids from Euphorbia paralias . Phytochemistry 2001; 58: 1135-1139
    CrossrefPubMedGoogle Scholar
  • 22 Jakupovic J, Jeske F, Morgenstern F, Tsichritzis F, Marco JA, Berendsohn W. Diterpenes from Euphorbia segetalis . Phytochemistry 1998; 47: 1583-1600
    CrossrefPubMedGoogle Scholar
  • 23 Corea G, Fattorusso C, Fattorusso E, Lanzotti V. Amygdaloidins A–L, twelve new 13 α-OH jatrophane diterpenes from Euphorbia amygdaloides L. Tetrahedron 2005; 61: 4485-4494
    CrossrefPubMedGoogle Scholar
  • 24 Öksüz S, Gürek F, Yang SW, Lin LZ, Cordell GA, Pezzuto JM, Wagner H, Lotter H. Paralinones A and B, novel diterpene esters from Euphorbia paralias . Tetrahedron 1997; 53: 3215-3222
    CrossrefPubMedGoogle Scholar
  • 25 Gotta H, Adolf W, Opferkuch HJ, Hecker E. On the active principles of the Euphorbiaceae, IX a ingenane type diterpene esters from five Euphorbia species. Z Naturforsch B 1984; 39: 683-694
    PubMedGoogle Scholar
  • 26 Jakupovic J, Morgenstern T, Marco JA, Berendsohn W. Diterpenes from Euphorbia paralias . Phytochemistry 1998; 47: 1611-1619
    CrossrefPubMedGoogle Scholar
  • 27 Madureira AM, Gyémánt N, Ascenso JR, Abreu PM, Molnar J, Ferreira MJ. Euphoportlandols A and B, tetracylic diterpene polyesters from Euphorbia portlandica and their anti-MDR effects in cancer cells. J Nat Prod 2006; 69: 950-953
    CrossrefPubMedGoogle Scholar
  • 28 Barile E, Lanzotti V. Biogenetical related highly oxygenated macrocyclic diterpenes from sea spurge Euphorbia paralias . Org Lett 2007; 9: 3603-3606
    CrossrefPubMedGoogle Scholar
  • 29 Wan LS, Shao LD, Fu L, Xu J, Zhu GL, Peng XR, Li XN, Li Y, Qui MH. One-step semisynthesis of a segetane diterpenoid from a jatrophane precursor via a Diels-Alder reaction. Org Lett 2016; 18: 496-499
    CrossrefPubMedGoogle Scholar
  • 30 Riina R, Peirson JA, Geltman DV, Molero J, Frajman B, Pahlevani A, Barres L, Morawetz JJ, Salmaki Y, Zarre S, Kryukov A, Bruyns P, Berry PE. A worldwide molecular phylogeny and classification of the leafy spurges, Euphorbia subgenus Esula (Euphorbiaceae). Taxon 2013; 62: 316-342
    CrossrefPubMedGoogle Scholar
  • 31 Shavarda AL, Geltman DV. Skeleton types of diterpenoids and the system of genus Euphorbia (Euphorbiaceae). Rastitelnye Resursy 2017; 53: 163-195
    PubMedGoogle Scholar
  • 32 Cornwell MM, Pastan I, Gottesman MM. Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J Biol Chem 1987; 262: 2166-2170
    PubMedGoogle Scholar
  • 33 Domínguez-Álvarez E, Gajdács M, Spengler G, Palop JA, Marć MA, Kieć-Kononowicz K, Amaral L, Molnár J, Jacob C, Handzlik J, Sanmartín C. Identification of selenocompounds with promising properties to reverse cancer multidrug resistance. Bioorg Med Chem Lett 2016; 26: 2821-2824
    CrossrefPubMedGoogle Scholar
  • 34 Molnár J, Gyémánt N, Mucsi I, Molnár A, Szabó M, Körtvélyesi T, Varga A, Molnár P, Tóth G. Modulation of multidrug resistance and apoptosis of cancer cells by selected carotenoids. In Vivo 2004; 18: 237-244
    PubMedGoogle Scholar