Five New Diarylbutyrolactones and Sesquilignans from Saussurea medusa and Their Inhibitory Effects on LPS-induced NO Production

Abstract

Five new diarylbutyrolactones and sesquilignans (1a/1b – 4), including one pair of enantiomers (1a/1b), together with 10 known analogues (5 – 14), were isolated from the whole plants of Saussurea medusa. Compound 1 was found to possess an unusual 7,8′-diarylbutyrolactone lignan structure. Separation by chiral HPLC analysis led to the isolation of one pair of enantiomers, (+)-1a and (−)-1b. The structures of the new compounds were elucidated by extensive spectroscopic data. All compounds, except compounds 5, 7 and 9, were isolated from S. medusa for the first time. Moreover, compounds 1 –  4, 8 and 10 – 14 had never been obtained from the genus Saussurea previously. Compounds (+)- 1a, 2, 5, 7, and 9 – 11 were found to inhibit the lipopolysaccharide (LPS)-induced release of NO by RAW264.7 cells with IC₅₀ values ranging from 10.1 ± 1.8 to 41.7 ± 2.1 µM. Molecular docking and iNOS expression experiments were performed to examine the interactions between the active compounds and the iNOS enzyme.

Key words

Saussurea medusa - Asteraceae - diarylbutyrolactone lignan - sesquilignan - anti-inflammatory activity - molecular docking

• References

• 1 The angiosperm phylogeny group. An update of the angiosperm phylogeny group classification for the orders and families of flowering plants: APG IV. Bot J Linn Soc 2016; 181: 1-20
• 2 Li HH, Qiu J, Chen FD, Lv XF, Fu CX, Zhao DX, Hua XJ, Zhao Q. Molecular characterization and expression analysis of dihydroflavonol 4-reductase (DFR) gene in Saussurea medusa . Mol Biol Rep 2012; 39: 2991-2999
• 3 Northwest Institute of Plateau Biology. The Chinese Academy of Sciences. The Tibetan Medicine Glossary. Xining: Qinghai Peopleʼs Press; 1991: 222-223
• 4 Yu RX, Jiang L, Mei LJ, Tao YD, Yu RT, Xia XC. Anti-inflammatory effects of alcohol extract from Saussurea medusa Maxim. against lipopolysaccharides-induced acute lung injury mice. Int J Clin Exp Medic Res 2019; 3: 112-118
• 5 Pescitelli G, Bruhn T. Good computational practice in the assignment of absolute configurations by TDDFT calculations of ECD spectra. Chirality 2016; 28: 466-474
• 6 Liu X, Zhang BF, Yang L, Chou GX, Wang ZT. Four new compounds from Imperata cylindrica . J Nat Med 2013; 68: 295-301
• 7 Mali RS, Babu KN. Efficient synthesis of α-benzylidene-γ-methyl-γ- butyrolactones. Helv Chim Acta 2002; 85: 3525-3531
• 8 Datta A, Ila H, Junjappa H. Polarized ketene dithioacetals 63. Tetrahedron 1987; 43: 5367-5374
• 9 Fischer J, Reynolds AJ, Sharp LA, Sherburn MS. Radical carboxyarylation approach to lignans. Total synthesis of (−)-arctigenin, (−)-matairesinol, and related natural products. Org Lett 2004; 6: 1345-1348
• 10 Corrie J, Green GH, Ritchie E, Taylor WC. The chemical constituents of Australian Zanthoxylum species. V. The constituents of Z. pluviatile Hartley; the structures of two new lignans. Aust J Chem 1970; 23: 133-145
• 11 Gan ML, Zhang YL, Sheng L, Liu MT, Song WX, Zi JC, Yang YC, Fan XN, Shi JG, Hu JF, Sun JD, Chen NH. Glycosides from the root of Iodes cirrhosa . J Nat Prod 2008; 71: 647-654
• 12 Frelek J, Szczepek WJ. [Rh₂(OCOCF₃)₄] as an auxiliary chromophore in chiroptical studies on steroidal alcohols. Tetrahedron Asymmetry 1999; 10: 1507-1520
• 13 Frelek J, Klimek A, Ruskowska P. Dinuclear transition metal complexes as auxiliary chromophores in chiroptical studies on bioactive compounds. Curr Org Chem 2003; 7: 1081-1104
• 14 Jang YP, Kim SR, Kim YC. Neuroprotective dibenzylbutyrolactone lignans of Torreya nucifera . Planta Med 2001; 67: 470-472
• 15 Tiwari AK, Srinivas PV, Kumar SP, Rao JM. Free radical scavenging active components from Cedrus deodara . J Agric Food Chem 2001; 49: 4642-4645
• 16 Chang H, Wang YW, Gao X, Song ZH, Awale S, Han N, Liu ZH, Yin J. Lignans from the root of Wikstroemia indica and their cytotoxic activity against PANC-1 human pancreatic cancer cells. Fitoterapia 2017; 31: 1-27
• 17 Piccinelli AL, Mahmood N, Mora G, Poveda L, Simone FD, Rastrelli L. Anti-HIV activity of dibenzylbutyrolactone-type lignans from Phenax species endemic in Costa Rica. J Pharm Pharmacol 2005; 57: 1109-1115
• 18 Tuchinda P, Kornsakulkarn J, Pohmakotr M, Kongsaeree P, Prabpai S, Yoosook C, Kasisit J, Napaswad C, Sophasan S, Reutrakul V. Dichapetalin-type triterpenoids and lignans from the aerial parts of Phyllanthus acutissima . J Nat Prod 2008; 71: 655-663
• 19 Matsumoto T, Hosono-Nishiyama K, Yamada H. Antiproliferative and apoptotic effects of butyrolactone lignans from Arctium lappa on leukemic cells. Planta Med 2006; 72: 276-278
• 20 Umehara K, Sugawa A, Kuroyanagi M, Ueno A, Taki T. Studies on differentiation-inducers from Arctium fructus. Chem Pharm Bull 1993; 41: 1774-1779
• 21 Zhao F, Wang L, Liu K. In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway. J Ethnopharmacol 2009; 122: 457-462
• 22 Kou XJ, Qi SM, Dai WX, Luo L, Yin ZM. Arctigenin inhibits lipopolysaccharide-induced iNOS expression in RAW264.7 cells through suppressing JAK-STAT signal pathway. Int Immunopharmacol 2011; 11: 1095-1102
• 23 Cuong TD, Hung TM, Kim JC, Kim EH, Woo MH, Choi JS, Lee JH, Min BS. Phenolic compounds from Caesalpinia sappan heartwood and their anti-inflammatory activity. J Nat Prod 2012; 75: 2069-2075
• 24 Zhang Y, Liu JZ, Wang MY, Sun CJ, Li XB. Five new compounds from Hosta plantaginea flowers and their anti-inflammatory activities. Bioorg Chem 2020; 95: 1-7