Cytotoxic and Anti-inflammatory Terpenoids from the Whole Plant of Vaccinium emarginatum

Abstract

Two new Δ¹² ursene-type triterpenoid coumaroyl esters (1 and 2), one new Δ^7,15 isopimarane-type diterpenoid glycoside (20), and two new irido-δ-lactone-type iridoids (21 and 22), together with 17 known pentacyclic triterpenoids (3 – 19), were isolated during the phytochemical investigation of a methanol extract of the whole plant of Vaccinium emarginatum. Their structures were determined by detailed analysis of standard spectroscopic data (MS, IR, 1D, and 2D NMR) and comparison with data of known analogs. The isolates were evaluated for their cytotoxicity against the PC-3 and Du145 prostate cancer cell lines (as assessed by an MTT cell proliferation assay), as well as for their anti-inflammatory activity via the inhibition of nitric oxide production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among the isolates, the triterpenoid coumaroyl and feruloyl esters (1, 3, and 4) exhibited strong cytotoxicity against PC-3 prostate cancer cells, with 85.6 – 90.2% inhibition at 10.0 µg/mL. The pomolic acid coumaroyl and feruloyl esters (1 and 3) also showed moderate anti-inflammatory activity against nitric oxide production in lipopolysaccharide-induced RAW 264.7 cells, with 59.2 (± 1.0) and 47.1% (± 0.2) inhibition at 12.5 µg/mL, respectively.

Key words

Vaccinium emarginatum - Ericaceae - terpenoids - cytotoxicity - anti-inflammatory activity

Publication History

Received: 15 July 2019

Accepted after revision: 24 May 2020

Article published online:
09 July 2020

• References

• 1 Song GQ, Hancock JF. Vaccinium . In: Kole C. ed. Wild Crop Relatives: Genomic and breeding Resources, Temperate Fruits. Heidelberg: Springer; 2011: 197-221
• 2 Su Z. Anthocyanins and flavonoids of Vaccinium L. Pharm Crop 2012; 3: 7-37
• 3 Szajdek A, Borowska EJ. Bioactive compounds and health-promoting properties of berry fruits: A review. Plant Foods Hum Nutr 2008; 63: 147-156
• 4 Viskelis P, Rubinskienė M, Jasutienė I, Šarkinas A, Daubaras R, Česonienė L. Anthocyanins, antioxidative, and antimicrobial properties of American cranberry (Vaccinium macrocarpon Ait.) and their press cakes. J Food Sci 2009; 74: C157-C161
• 5 Kylli P, Nohynek L, Puupponen-Pimiä R, Westerlund-Wikström B, Leppänen T, Welling J, Moilanen E, Heinonen M. Lingonberry (Vaccinium vitis-idaea) and European cranberry (Vaccinium microcarpon) proanthocyanidins: Isolation, identification, and bioactivities. J Agric Food Chem 2011; 59: 3373-3384
• 6 Rocha DMUP, Caldas APS, da Silva BP, Hermsdorff HH, Alfenas RCG. Effects of blueberry and cranberry consumption on type 2 diabetes glycemic control: A systematic review. Crit Rev Food Sci Nutr 2019; 59: 1816-1828
• 7 Llivisaca S, Manzano P, Ruales J, Flores J, Mendoza J, Peralta E, Cevallos-Cevallos JM. Chemical, antimicrobial, and molecular characterization of mortiño (Vaccinium floribundum Kunth) fruits and leaves. Food Sci Nutr 2018; 6: 934-942
• 8 Neto CC. Cranberry and its phytochemicals: a review of in vitro anticancer studies. J Nutr 2007; 137: 186S-193S
• 9 Johnson SA, Arjmandi BH. Evidence for anti-cancer properties of blueberries: a mini-review. Anticancer Agents Med Chem 2013; 13: 1142-1148
• 10 Liu F, Wang YN, Li Y, Ma SG, Qu J, Liu YB, Niu CS, Tang ZH, Li YH, Li L, Yu SS. Triterpenoids from the twigs and leaves of Rhododendron latoucheae by HPLC-MS-SPE-NMR. Tetrahedron 2019; 75: 296-307
• 11 Tanachatchairatana T, Bremner JB, Chokchaisiri R, Suksamrarn A. Antimycobacterial activity of cinnamate-based esters of the triterpenes betulinic, oleanolic and ursolic acids. Chem Pharm Bull 2008; 56: 194-198
• 12 Sevindik H, Ozgen U, Atila A, Ozturk Er H, Kazaz C, Duman H. Phtytochemical studies and quantitative HPLC analysis of rosmarinic acid and luteolin 5-O-β-D-glucopyranoside on Thymus praecox subsp. grossheimii var. grossheimii . Chem Pharm Bull 2015; 63: 720-725
• 13 Ding P, Wang KW. Chemical constituents of Euscaphis japonica . Chem Nat Compd 2018; 54: 393-395
• 14 Kojima H, Ogura H. Configurational studies on hydroxy groups at C-2, 3 and 23 or 24 of oleanene and ursene-type triterpenes by NMR spectroscopy. Phytochemistry 1989; 28: 1703-1710
• 15 Hirai N, Sugie M, Wada M, Lahlou E, Kamo T, Yoshida R, Tsuda M, Ohigashi H. Triterpene phytoalexins from strawberry fruit. Biosci Biotechnol Biochem 2000; 64: 1707-1712
• 16 Wen DX, Chen ZL. A dimeric sinapaldehyde glucoside from Ilex rotunda . Phytochemistry 1996; 41: 657-659
• 17 Sakakibara J, Kaiya T, Fukuda H. Triterpenoids from Enkianthus campanulatus . Phytochemistry 1984; 23: 627-630
• 18 Martinez A, Rivas F, Perojil A, Parra A, Garcia-Granados A, Fernandez-Vivas A. Biotransformation of oleanolic and maslinic acids by Rhizomucor miehei . Phytochemistry 2013; 94: 229-237
• 19 Zebiri I, Haddad M, Duca L, Sauvain M, Paloque L, Cabanillas B, Rengifo E, Behr JB, Voutquenne-Nazabadioko L. Biological activities of triterpenoids from Poraqueiba sericea stems. Nat Prod Res 2017; 31: 1333-1338
• 20 An JP, Ha TK, Kim J, Cho TO, Oh WK. Protein tyrosine phosphatase 1B inhibitors from the stems of Akebia quinata . Molecules 2016; 21: 1091
• 21 Zhang ZX, Li HH, Dong LL, Fan GX, Fei DQ. Chemical constituents of the roots of Ligularia lapathifolia . Chem Nat Compd 2015; 51: 375-377
• 22 Salae AW, Rodjun A, Karalai C, Ponglimanont C, Chantrapromma S, Kanjana-Opas A, Tewtrakul S, Fun HK. Potential anti-inflammatory diterpenes from Premna obtusifolia . Tetrahedron 2012; 68: 819-829
• 23 Seca AML, Pinto DCGA, Silva AMS. Structural elucidation of pimarane and isopimarane diterpenoids: The ¹³C NMR contribution. Nat Prod Commun 2008; 3: 399-412
• 24 Pérez AJ, Simonet AM, Calle JM, Pecio Ł, Guerra JO, Stochmal A, Macías FA. Phytotoxic steroidal saponins from Agave offoyana leaves. Phytochemistry 2014; 105: 92-100
• 25 Aquino R, De Tommasi N, De Simone F, Pizza C. Triterpenes and quinovic acid glycosides from Uncaria tomentosa . Phytochemistry 1997; 45: 1035-1040
• 26 Ohashi K, Kojima H, Tanikawa T, Okumura Y, Kawazoe K, Tatara N, Shibuya H, Kitagawa I. Indonesian medicinal plants. IX. Chemical structures of gongganosides A, B, and C, three new quinovic acid glycosides from the bark of Bhesa paniculata (Celastraceae). Chem Pharm Bull (Tokyo) 1994; 42: 1596-1600
• 27 Schwarz S, Siewert B, Xavier NM, Jesus AR, Rauter AP, Csuk R. A “natural” approach: synthesis and cytoxicity of monodesmosidic glycyrrhetinic acid glycosides. Eur J Med Chem 2014; 72: 78-83
• 28 Khan HPA, Das D, Chakraborty TK. Application of Cp2TiCl-promoted radical cyclization: a unified strategy for the syntheses of iridoid monoterpenes. J Org Chem 2018; 83: 6086-6092
• 29 Uesato S, Shan X, Inouye H, Shingu T, Inouet M, Doi M. Absolute structure of gibboside, an iridoid glucoside from Patrinia gibbosa . Phytochemistry 1987; 26: 561-564
• 30 Topcu G, Che CT, Cordell GA, Ruangrungsi N. Iridolactones from Alyxia reinwardti . Phytochemistry 1990; 29: 3197-3199
• 31 Mu LH, Wang YN, Liu L, Liu P. New iridoids from the whole plant of Patrinia heterophylla . Chem Nat Compd 2019; 55: 32-35
• 32 Li N, Di L, Gao WC, Wang KJ, Zu LB. Cytotoxic iridoids from the roots of Patrinia scabra . J Nat Prod 2012; 75: 1723-1728
• 33 Liao CR, Kuo YH, Ho YL, Wang CY, Yang CS, Lin CW, Chang YS. Studies on cytotoxic constituents from the leaves of Elaeagnus oldhamii Maxim. in non-small cell lung cancer A549 cells. Molecules 2014; 19: 9515-9534
• 34 Sun H, Fang WS, Wang WZ, Hu C. Structure-activity relationships of oleanane- and ursane-type triterpenoids. Bot Stud 2006; 47: 339-368
• 35 Kuo HP, Chuang TC, Tsai SC, Tseng HH, Hsu SC, Chen YC, Kuo CL, Kuo YH, Liu JY, Kao MC. Berberine, an isoquinoline alkaloid, inhibits the metastatic potential of breast cancer cells via Akt pathway modulation. J Agric Food Chem 2012; 60: 9649-9658