New Hirsutinolide-Type Sesquiterpenoids from Vernonia cinerea Inhibit Nitric Oxide Production in LPS-Stimulated RAW264.7 Cells

Abstract

Phytochemical investigation of ethanol extracts from two Taiwanese collections of Vernonia cinerea resulted in the isolation of eighteen hirsutinolide-type sesquiterpenoids, including seven new ones designated as vernolides E – K (1–7). All structures were determined by a combination of detailed spectroscopic analyses (NMR and MS) and comparison with reported data. In an in vitro anti-inflammatory assay, compounds 3, 7, 9, 11, and 14 exhibited strong inhibitory activities toward NO production by LPS-induced RAW264.7 macrophages, with IC₅₀ values of 1.18, 0.85, 0.66, 0.71 and 0.45 µM, respectively, without affecting cellular viability at 40 µM. Preliminary structure-activity relationships indicate that the ester groups at C-8 and C-13 may enhance inhibition of NO production.

Key words

Vernonia cinerea - Asteraceae - hirsutinolide - vernolide - anti-inflammatory - RAW264.7 cells - nitric oxide

^* These authors contributed equally to this work.

• References

• 1 Chiu NY, Chang KH. The illustrated medicinal Plants of Taiwan, Vol. 1. Taipei: SMC Publishing; 1983: 229
• 2 Iwalewa E, Iwalewa O, Adeboye J. Analgesic, antipyretic, anti-inflammatory effects of methanol, chloroform and ether extracts of Vernonia cinerea less leaf. J. Ethnopharmacol 2003; 86: 229-234
• 3 Pratheeshkumar P, Kuttan G. Ameliorative action of Vernonia cinerea L. on cyclophosphamide-induced immunosuppression and oxidative stress in mice. Inflammopharmacology 2010; 18: 197-207
• 4 Latha R, Geetha T, Varalakshmi P. Effect of Vernonia cinerea less flower extract in adjuvant-induced arthritis. Gen Pharmacol 1998; 31: 601-606
• 5 Mazumder U, Gupta M, Manikandan L, Bhattacharya S, Haldar P, Roy S. Evaluation of anti-inflammatory activity of Vernonia cinerea Less. extract in rats. Phytomedicine 2003; 10: 185-188
• 6 Adeboye JO, Asije W, Awe SO. Diuretic and antidiuretic diuretic of the leaf extracts of Vernonia cinerea (Less) (Fam. Compositae). Phytother Res 1997; 11: 454-456
• 7 Gupta M, Mazumder UK, Manikandan L, Bhattacharya S, Haldar PK, Roy S. Evaluation of antipyretic potential of Vernonia cinerea extract in rats. Phytother Res 2003; 17: 804-806
• 8 Bohlmann F, Brindöpke G, Rastogi RC. A new type of germacranolide from Vernonia species. Phytochemistry 1978; 17: 475-482
• 9 Chea A, Hout S, Long C, Marcourt L, Faure R, Azas N, Elias R. Antimalarial activity of sesquiterpene lactones from Vernonia cinerea . Chem Pharm Bull 2006; 54: 1437-1439
• 10 Chen X, Zhan ZJ, Zhang XW, Ding J, Yue JM. Sesquiterpene lactones with potent cytotoxic activities from Vernonia chinensis . Planta Med 2005; 71: 949-954
• 11 Kos O, Castro V, Murillo R, Poveda L, Merfort I. Ent-kaurane glycosides and sesquiterpene lactones of the hirsutinolide type from Vernonia triflosculosa . Phytochemistry 2006; 67: 62-69
• 12 Kuo YH, Kuo YJ, Yu AS, Wu MD, Ong CW, Kuo LMY, Huang JT, Chen CF, Li SY. Two novel sesquiterpene lactones, cytotoxic vernolide-A and -B, from Vernonia cinerea . Chem Pharm Bull 2003; 51: 425-426
• 13 Youn UJ, Park EJ, Kondratyuk TP, Simmons CJ, Borris RP, Tanamatayarat P, Wongwiwatthananukit S, Toyama O, Songsak T, Pezzuto JM, Chang LC. Anti-inflammatory sesquiterpene lactones from the flower of Vernonia cinerea . Bioorg Med Chem Lett 2012; 22: 5559-5562
• 14 Yang YL, Chang SM, Wu CC, Hsieh PW, Chen SL, Chang FR, Hung WC, Issa HH, Wu YC. Cytotoxic sesquiterpene lactones from Pseudoelephantopus spicatus . J Nat Prod 2007; 1761-1765
• 15 Borkosky S, Bardón A, Catalán CA, Díaz JG, Herz W. Glaucolides, hirsutinolides and other sesquiterpene lactones from Vernonanthura pinguis . Phytochemistry 1997; 44: 465-470
• 16 Huo J, Yang SP, Xie BJ, Liao SG, Lin LP, Ding J, Yue JM. Cytotoxic sesquiterpenoids from Vernonia bockiana . J Asian Nat Prod Res 2008; 10: 571-575
• 17 Qureshi AA, Tan X, Reis JC, Badr MZ, Papasian CJ, Morrison DC, Qureshi N. Inhibition of nitric oxide in LPS-stimulated macrophages of young and senescent mice by δ-tocotrienol and quercetin. Lipids Health Dis 2011; 10: 239
• 18 Dong Z, Gu Q, Cheng B, Cheng ZB, Tang GH, Sun ZH, Zhang JS, Bao JM, Yin S. Natural nitric oxide (NO) inhibitors from Aristolochia mollissima . RSC Adv 2014; 4: 55036-55043