Bioactivity-Guided Isolation of Cytotoxic Sesquiterpenes and Flavonoids from Anthemis ruthenica

Abstract

A new eudesmanolide sesquiterpene, sivasinolide 6-O-angelate (1), was isolated from the aerial parts of Anthemis ruthenica together with the known compounds chrysanin (2), tanacin (3), 3β-hydroxycostunolide (4), centauridin (5), and centaureidin (6). The compounds were obtained by means of bioactivity-guided fractionation from the CHCl₃ extract of the herb, which displayed high cytotoxic activity. The structures were determined by UV, HR‐ESI‐MS, and high-field 1D and 2D NMR spectral analyses, affording complete ¹H- and ¹³C‐NMR assignments for all compounds. The cytotoxic activities of the isolated sesquiterpenes and flavonoids were assessed against cervical adenocarcinoma HeLa, breast adenocarcinoma MCF7, and skin epidermoid carcinoma A431 cells using the MTT assay. It was found that, apart from centaureidin (6), which is extremely active (IC₅₀ 0.082, 0.13, and 0.35 µM on the HeLa, MCF7, and A431 cell lines, respectively), all these compounds exert high or moderate tumor cell-growth inhibitory activity (IC₅₀ 3.42–58.15 µM).

Key words

Anthemis ruthenica - Asteraceae - cytotoxic activity - sesquiterpenes - flavonols

References

• 1 Tutin T G, Heywood V H, Burges N A, Moore D M, Valentine D H, Walters S M, Webb D A. Flora Europea, Vol. 4. Cambridge, London, New York, Melbourne; Cambridge University Press 1976
• 2 Vujisic L, Vuckovic I, Tesevic V, Dokovic D, Ristic M S, Janackovic P, Milosavljevic S. Comparative examination of the essential oils of Anthemis ruthenica and A. arvensis wild-growing in Serbia.  Flavour Fragrance J. 2006;  21 458-461
• 3 Savin K, Ivanic R, Miric M. Anthemis ruthenica Mb, composition of its volatile oil.  Acta Pharm Jugoslav. 1981;  31 243-247
• 4 Réthy B, Zupkó I, Csupor-Löffler B, Hajdú Z, Máthé I, Hohmann J, Rédei T, Falkay G. Cytotoxic activity of Hungarian Asteraceae species against human cancer cell lines, Part I.  Phytother Res. 2007;  21 1200-1208
• 5 Gören N, Bozok-Johansson C, Jakupovic J, Lin L J, Shieh H L, Cordell G A, Celik N. Sesquiterpene lactones with antibacterial activity from Tanacetum densum subsp. sivasicum.  Phytochemistry. 1992;  31 101-104
• 6 Konstantinopoulou M, Karioti A, Skaltsas S, Skaltsa H. Sesquiterpene lactones from Anthemis altissima and their anti-Helicobacter pylori activity.  J Nat Prod. 2003;  66 699-702
• 7 Triana J, López M, Rico M, González-Platas J, Quintana J, Estévez F, León F, Bermejo J. Sesquiterpenoid derivatives from Gonospermum elegans and their cytotoxic activity for HL-60 human promyelocytic cells.  J Nat Prod. 2003;  66 943-948
• 8 Bohlmann F, Jakupovic J, Ahmed M, Schuster A. Sesquiterpene lactones and other constituents from Schistostephium species.  Phytochemistry. 1983;  22 1623-1636
• 9 Sigstad E E, Catalán C A N, Gutiérrez A B, Diaz J G, Goedken V L, Herz W. Guaianolides and germacranolides from Stevia grisebachiana.  Phytochemistry. 1991;  30 1933-1940
• 10 Horie T, Ohtsuru Y, Shibata K, Yamashita K, Tsukayama M, Kawamura Y. ¹³C NMR spectral assignment of the A-ring of polyoxygenated flavones.  Phytochemistry. 1998;  47 865-874
• 11 Rashid M A, Amstrong J A, Gray A I, Waterman P G. Alkaloids, flavonols and coumarins from Drummondita hassellii and D. calida.  Phytochemistry. 1992;  31 1265-1269
• 12 Barberá O, Marco J A, Sanz J F, Sánchez-Parareda J. 3-Methoxyflavones and coumarins from Artemisia incanascens.  Phytochemistry. 1986;  25 2357-2360
• 13 Glasl S, Mucaji P, Werner I, Presser A, Jurenitsch J. Sesquiterpenes and flavonoid aglycones from a Hungarian taxon of the Achillea millefolium group.  Z Naturforsch C. 2002;  57 976-982
• 14 Doskotch R W, El-Feraly F S, Hufford C D. Sesquiterpene lactones from pyrethrum flowers.  Can J Chem. 1971;  49 2103-2110
• 15 Gören N, Tahtasakai E. Sesquiterpenoids from Tanacetum argenteum subsp. canum var. canum.  Phytochemistry. 1997;  45 107-109
• 16 Bohlmann F, Jakupovic J, Ahmed M, Schuster A. Sesquiterpene lactones and other constituents from Schistostephium species.  Phytochemistry. 1983;  22 1623-1636
• 17 Yunusov A I, Abdullaev N D, Kasymov S Z, Sidyakin G, Yagudaev M R. Structure of the sesquiterpene lactone tanacin.  Khim Prir Soedin. 1976;  170-174
• 18 Staneva J D, Todorova M N, Evstatieva L N. Sesquiterpene lactones as chemotaxonomic markers in genus Anthemis.  Phytochemistry. 2008;  69 607-618
• 19 Beutler J A, Hamel E, Vlietinck A J, Haemers A, Rajan P, Roitman J N, Cardellina J H, Boyd M R. Structure-activity requirements for flavone cytotoxicity and binding to tubulin.  J Med Chem. 1998;  41 2333-2338
• 20 Bruno M, Rosselli S, Maggio A, Raccuglia R A, Bastow K F, Wu C C, Lee K H. Cytotoxic activity of some natural and synthetic sesquiterpene lactones.  Planta Med. 2005;  71 1176-1178
• 21 Kupchan S M, Eakin M A, Thomas A M. Tumor inhibitors. 69. Structure-cytotoxicity relationships among the sesquiterpene lactones.  J Med Chem. 1971;  14 1147-1152
• 22 Schmidt T J, Heilmann J. Quantitative structure-cytotoxicity relationships of sesquiterpene lactones derived from partial charge (Q)-based fractional accessible surface area descriptors (Q_frASAs).  Quant Struct Act Relat. 2002;  21 276-287