ISOLATION OF BIOACTIVE COMPOUNDS FROM CENTAUREA AEGYPTIACA
Objective: In a previous study, Centaurea aegyptiaca ethanol and ethyl acetate extracts showed potent cytotoxic effects against laryngeal (HEP2) and hepatic (HEPG2) carcinoma cell lines. Additionally, two novel compounds were isolated and identified. The aim of this study is to continue isolating and identifying another compound (s) that may, also, be responsible for this potent biological activity.
Methods: C. aegyptiaca dried aerial parts were extracted with ethanol and ethyl acetate. Both extracts were chromatographed separately to afford seven guaianolides that were identified using different spectroscopic methods. Moreover, compounds 1-7 were evaluated for their cytotoxicity (IC50, ÂµM) against HEP2 and HEPG2 cells in comparison to the normal fibroblasts (BHK) using sulforhodamine B assay. Doxorubicin was used as a positive control.
Results: Seven sesquiterpene lactones, centaurepensin, also known as chlorohyssopifolin A (1), 8Î±-hydroxy-11Î±, 13-dihydrozaluzanin C (2), chlorohyssopifolin B (3), desacylcynaropicrin (4), chlorohyssopifolin C, acroptilin (5), subluteolide (6), and solstitiolide (7) were isolated from C. aegyptiaca extracts and identified. This is the first report on the occurrence of 2, 4, 5 and 6 in C. aegyptiaca. Compounds 1-4 and 6 exhibited selective cytotoxic effects against HEP2 and HEPG2 cells. However, compounds 1 and 7 showed the highest activities against HEP2 with IC50 values of 10.6Â±0.02 and 10.9Â±0.03 ÂµM, respectively. Moreover, compound 3 was the most potent one against HEPG2 cells with IC50value of 13.8Â±0.05 ÂµM.
Conclusions: Chemical investigation of C. aegyptiaca ethanol and ethyl acetate extracts led to the isolation and identification of seven guaianolides. These compounds exhibited good cytotoxic activities against HEP2 and HEPG2 cell lines.
2. Runguphan W, Qu X, E Oâ€™Connor S. Integrating carbon-halogen bond formation into medicinal plant metabolism. Nature 2010;468:461-4.
3. Blunt J, Copp B, Munro M, Northcote P, Prinsep M. Marine natural products. Nat Prod Rep 2004;21:1-49.
4. Dembitsky VM, Tolstikov GA. Chlorine-containing sesquiterpenes of higher plants. Chem Sustainable Dev 2002; 10:363-70.
5. Koukoulitsa E, Skaltsa H, Karioti A, Demetzos C, Dimas K. Bioactive sesquiterpene lactones from Centaurea species and their cytotoxic/cytostatic activity against human cell lines in vitro. Planta Med 2002;68:649-52.
6. Saroglou V, Karioti A, Demetzos C, Dimas K, Skaltsa H. Sesquiterpene lactones from Centaurea spinosa and their antibacterial and cytotoxic activities. J Nat Prod 2005;68:1404-7.
7. Talhouk RS, El-Jouni W, Baalbaki R, Gali-Muhtasib H, Kogan J, Talhouk SN. Anti-inflammatory bio-activities in a water extract of Centaurea ainetensis. J Med Plants Res 2008;2:24-33.
8. Koukoulitsa C, Germichalos G, Skaltsa H. VolSurf analysis of pharmacokinetic properties for several antifungal sesquiterpene lactones isolated from greek Centaurea sp. J Comput Aided Mol Des 2005;19:617-23.
9. Skaltsa H, Lazari D, Panagouleas C, Georgiadou E, Garcia B, Sokovic M. Sesquiterpene lactones from Centaurea thessala and Centaurea attica antifungal activity. Phytochemistry 2000; 55:903-8.
10. Medjroubi K, Bouderdara N, Benayache F, Akkal S, Seguin E, Tillequin F. Sesquiterpene lactones of Centaurea nicaensis. Chem Nat Compd 2003;39:506-7.
11. Saikali M, Ghantous A, Halawa R, Talhouk S, Saliba N, Darwiche N. Sesquiterpene lactones isolated from indigenous Middle Eastern plants inhibit tumor promoter-induced transformation of JB6 cells. BMC Complementary Altern Med 2012;12:89.
12. Erol-Dayi O, Pekmez M, Bona M, Aras-Perk A, Arda N. Total phenolic contents, antioxidant activities and cytotoxicity of three Centaurea species: C. calcitrapa subsp. calcitrapa, C. ptosimopappa and C. spicata. Free Radicals Antioxidants 2011;1:31-6.
13. Scotti M, Fernandez M, Ferreira M, Emerenciano V. Quantitative structure-activity relationship of sesquiterpene lactones with cytotoxic activity. Bioorg Med Chem 2007;15:2927-34.
14. Sary HG, Singab AB, Orabi KY. New cytotoxic guaianolides from Centaurea aegyptiaca. Nat Prod Commun 2016;11:711-4.
15. Harley-Mason J, Hewson AT, Kennard O, Pettersen RC. Isolation of centaurepensin, a guaianolide sesquiterpene lactone ester containing two chlorine atoms. Determination of structure and absolute configuration by x-ray crystallography. J Chem Soc Chem Commun 1972;8:460-1.
16. Gonzalez AG, Bermejo J, Breton JL, Triana J. Constituents of Compositae. XV. Chlorohyssopifolin A and B, two new sesquiterpene lactones isolated from Centaurea hyssopifolia. Tetrahedron Lett 1972;20:2017-20.
17. Cassady JM, Abramson D, Cowall P, Chang CJ, McLaughlin JL, Aynehchi Y. Potential antitumor agents. Part 13. Centaurepensin: a cytotoxic constituent of Centaurea solstitialis and C. repens (Asteracea). J Nat Prod 1979;42:427-9.
18. Al-Easa HS, Mann J, Rizk AF. Guaianolides from Centaurea sinaica. Phytochemistry 1990;29:1324-5.
19. Bohlmann F, Chen ZL. Guaianolides from Ainsliaea fragrans. Phytochemistry 1982;21:2120-2.
20. Helal AM, Nakamura N, Meselhy MR, El-Fishawy AM, Hattori M, Mahran GH. Guaianolides from Centaurea scoparia. Phytochemistry 1997;45:551-4.
21. El Dahmy S, Bohlmann F, Sarg TM, Ateya A, Farrag N. New guaianolides from Centaurea aegyptica. Planta Med 1985; 2:176-7.
22. Rustaiyan A, Niknejad A, Zdero C, Ferdinand B. A guaianolide from Centaurea behen. Phytochemistry 1981;20:2427-9.
23. Choi S, Choi S, Lee K. Cytotoxic sesquiterpene lactones from Saussurea calcicola. Arch Pharm Res 2005;28:1142-6.
24. Gonzalez A, Bermejo J, Breton J, Massanet G, Triana J. Chlorophyssopifolin C, D, E and vahlenin, four new sesquiterpene lactones from Centaurea hyssopifolia. Phytochemistry 1974;13:1193-7.
25. Gonzalez AG, Bermejo J, Amaro JM, Massanet GM, Galindo A, Cabrera I. Chemical constituents of the compositae. Part 35. Sesquiterpene lactones from Centaurea linifolia vahl. Can J Chem 1978;56:491-4.
26. Merrill GB, Stevens KL. Sesquiterpene lactones from Centaurea solstitialis. Phytochemistry 1985;24:2013-8.
27. Massiot G, Toubiana R. Structure of subluteolide, a new guaianolide isolated from Vernonia sublutea (Compositae). C R Hebd SÃ©ances Acad Sci Ser C 1974;279:907-9.
28. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, et al. New colorimetric cytotoxic assay for anticancer-drug screening. J Natl Cancer Inst 1990;82:1107-12.
29. Gonzalez AG, Bermejo J, Breton JL, Massanet GM, Dominguez B, Amaro JM. The chemistry of the compositae. Part XXX1. l absolute configuration of the sesquiterpene lactones centaurepensin (Chlorohyssopifolin A), acroptilin (Chlorohyssopifolin C), and repin. J Chem Soc Perkin 1976;1:1663-6.
30. Hamburger M, Wolfender JL, Hostettmann K. Search for chlorinated sesquiterpene lactones in the neurotoxic thistle Centaurea solstitialis by liquid chromatography-mass spectrometry, and model studies on their possible artifactual formation. Nat Toxins 1993;1:315-27.
31. Li X, Liu J, Cai J, Cai P. Complete 1H and 13C data assignments of two new guaianolides isolated from Ainsliaea fragrans. Magn Reson Chem 2008;46:1070-3.
32. Youssef D, Frahm AW. Constituents of the Egyptian Centaurea scoparia; chlorinated guaianolides of the aerial parts. Planta Med 1994;60:267-71.