Isolation, Characterization, and In Vitro Cytotoxicity of New Sesquiterpenoids from Achillea clavennae

Abstract

Further phytochemical investigation of the aerial parts of Achillea clavennae has resulted in the isolation of three new sesquiterpene lactones: two highly oxygenated germacranolides (1, 2) and the iso-seco-guaianolide 9(R)-acetoxy-3-O-methyl-iso-seco-tanapartholide (3). Eight known compounds were also found, of which 9α-acetoxycanin (5), sintenin (6), and oleanolic acid (7) were detected for the first time. The structures of the isolated compounds were elucidated by combined spectroscopic methods (1D and 2D NMR, HRESIMS, CIMS, and FTIR). While the predominant metabolite germacranolide sintenin (6) was not cytotoxic, the new iso-seco-guaianolide (3) displayed cytotoxicity comparable to that of cisplatin and the lactone apressin (4), inducing partly apoptotic death in human U251 and rat C6 glioma cell lines.

Key words

Achillea clavennae L. - Asteraceae - sesquiterpene lactones - iso-seco-guaianolide - NMR - cytotoxicity - apoptosis

• References

• 1 Gajić M. Genus Achillea L. In: Josifović VM, editor Flora of Serbia VII. Belgrade: Serbian Academy of Sciences and Arts; 1975: 90-110
• 2 Trifunović SS. Comparative investigation of the chemical composition of some plant species of the genus Achillea L. [dissertation]. Belgrade: University of Belgrade, Faculty of Chemistry; 2006
• 3 Sia XT, Zhanga ML, Shi QW, Kiyota H. Chemical constituents of the plants in the genus Achillea . Chem Biodivers 2006; 3: 1163-1180
• 4 Valant-Vetschera KM, Wollenweber E. Exudate flavonoid aglycones in alpine species of Achillea sect. Ptarmica . Biochem Syst Ecol 2001; 29: 149-159
• 5 Maggioni G. Nicolò Chiavenna, Bellunese druggist of the sixteenth century and the contested discovery of umbelliferous absinthium (Achilea clavenae L.). Minerva Farm 1953; 2: 267-269
• 6 Skočibušić M, Bežić N, Dunkić V, Radonić A. Antibacterial activity of Achillea clavennae essential oil against respiratory tract pathogens. Fitoterapia 2004; 75: 733-736
• 7 Bežić N, Skočibušić M, Dunkić V, Radonić A. Composition and antimicrobial activity of Achillea clavennae L. essential oil. Phytother Res 2003; 17: 1037-1040
• 8 Stojanović G, Radulović N, Hashimoto T, Palić R. In vitro antimicrobial activity of extracts of four Achillea species: the composition of Achillea clavennae L. (Asteraceae) extract. J Ethnopharmacol 2005; 101: 185-190
• 9 Trifunović S, Vajs V, Juranić Z, Žižak Ž, Tešević V, Macura S, Milosavljević S. Cytotoxic constituents of Achillea clavennae from Montenegro. Phytochemistry 2006; 67: 887-893
• 10 Tsankova E, Kempe UJ, Norin T, Ognyanov I. Apressin, a guaianolide of the endoperoxide type from Achillea depressa . Phytochemistry 1981; 20: 1436-1438
• 11 Todorova M, Mustakerova E, Tsankova E. Sesquiterpene lactones from Achillea depressa Janka. Dokladi na Bulgarskata Akademiya na Naukite 2005; 58: 25-32
• 12 Goren N, Oksuz S, Ulubelen A. A sesquiterpene lactone, sintenin from Achillea sintenisii . Phytochemistry 1988; 27: 2346-2347
• 13 Mladenova K, Tsankova E, van Hung D. New sesquiterpenoids from Chrysanthemum indicum var. tuneful . Planta Med 1988; 54: 553-555
• 14 Meselhy MR. Constituents from Moghat, the Roots of Glossostemon bruguieri (Desf.). Molecules 2003; 8: 614-621
• 15 Long C, Sauleau P, David B, Lavaud C, Cassabois V, Ausseil F, Massiot G. Bioactive flavonoids of Tanacetum parthenium revisited. Phytochemistry 2003; 64: 567-569
• 16 Seebacher W, Simić N, Weis R, Saf R, Kunert O. Complete assignments of ¹H and ¹³C NMR resonances of oleanolic acid, 18α-oleanolic acid, ursolic acid and their 11-oxo derivatives. Magn Reson Chem 2003; 41: 636-638
• 17 Oksuz S, Ulubelen A, Tuzlaci E. Constituents of Achillea teretifolia . Fitoterapia 1990; 61: 283
• 18 Barrero AF, Alvarez-Manzaneda REJ, Alvarez-Manzaneda RR. Bisabolene derivatives and other constituents from Achillea odorata . Phytochemistry 1990; 29: 3213-3216
• 19 Bruno M, Bondi ML, Paternostro MP, Arnold NA, Diaz JG, Herz W. Bisabolenes from Achillea cretica . Phytochemistry 1996; 42: 737-740
• 20 Hewlett MJ, Begley MJ, Groenewegen WA, Heptinstall S, Knight DW, May J, Salan U, Toplis D. Sesquiterpene lactones from feverfew, Tanacetum parthenium: isolation, structural revision, activity against human blood platelet function and implications for migraine therapy. J Chem Soc [Perkin I] 1996; 16: 1979-1986
• 21 Huneck S, Zdero C, Bohlmann F. Seco-guaianolides and other constituents from Artemisia species. Phytochemistry 1986; 25: 883-889
• 22 Makiyi EF, Frade RFM, Lebl T, Jaffray EG, Cobb SE, Harvey AL, Slawin AMZ, Hay RT, Westwood NJ. Iso-seco-tanapartholides: isolation, synthesis and biological evaluation. Eur J Org Chem 2009; 33: 5711-5715
• 23 Tan RX, Jia ZJ, Jakupovic J, Bohlmann F, Huneck S. Sesquiterpene lactones from Artemisia rutifolia . Phytochemistry 1991; 30: 3033-3035
• 24 Zan K, Chen XQ, Fu Q, Shi SP, Zhou SX, Xiao MT, Tu PF. 10-Secoguaianolides from Artemisia anomala (Asteraceae). Biochem Syst Ecol 2010; 38: 431-434
• 25 Trifunović S, Milosavljević S, Vajs V, Macura S, Todorović N. Stereochemistry and conformations of natural 1,2-epoxy-guaianolides based on 1D and 2D NMR data and semiempirical calculations. Magn Reson Chem 2008; 46: 427-431
• 26 Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 2003; 21: 1624-1636
• 27 Csupor-Löffler B, Hajdú Z, Zupkó I, Réthy B, Falkay G, Forgo P, Hohmann J. Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines. Phytother Res 2009; 23: 672-676
• 28 Hu LH, Zou HB, Gong JX, Li HB, Yang LX, Cheng W, Zhou CX, Bai H, Guéritte F, Zhao Y. Synthesis and biological evaluation of a natural ester sintenin and its synthetic analogues. J Nat Prod 2005; 68: 342-348
• 29 Sadowski-Debbing K, Coy JF, Mier W, Hug H, Los M. Caspases – their role in apoptosis and other physiological processes as revealed by knock-out studies. Arch Immunol Ther Exp (Warsz) 2002; 50: 19-34
• 30 Krysko DV, Vanden Berghe T, DʼHerde K, Vandenabeele P. Apoptosis and necrosis: detection, discrimination and phagocytosis. Methods 2008; 44: 205-221
• 31 Chandra J, Samali A, Orrenius S. Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 2000; 29: 323-333
• 32 Ghantous A, Nasser N, Saab I, Darwiche N, Saliba NA. Structure–activity relationship of seco-tanapartholides isolated from Achillea falcata for inhibition of HaCaT cell growth. Eur J Med Chem 2009; 44: 3794-3797
• 33 Ahn H, Kim JY, Lee HJ, Kim YK, Ryu JH. Inhibitors of inducible nitric oxide synthase expression from Artemisia iwayomogi . Arch Pharm Res 2003; 26: 301-305
• 34 Bohlmann F, Zdero C, King HR, Robinson EH. Pseudoguaianolides and other sesquiterpene lactones from Gaillardia species. Phytochemistry 1984; 23: 1979-1988
• 35 Trajkovic V, Vuckovic O, Stosic-Grujicic S, Miljkovic D, Popadic D, Markovic M, Bumbasirevic V, Backovic A, Cvetkovic I, Harhaji L, Ramic Z, Mostarica Stojkovic M. Astrocyte-induced regulatory T cells mitigate CNS autoimmunity. Glia 2004; 47: 168-179
• 36 Kaludjerovic GN, Miljkovic D, Momcilovic M, Djinovic VM, Mostarica Stojkovic M, Sabo TJ, Trajkovic V. Novel platinum(IV) complexes induce rapid tumor cell death in vitro . Int J Cancer 2005; 116: 479-486