Diterpenes from Euphorbia myrsinites and Their Anti-inflammatory Property^{[ # ]}

Abstract

Euphorbia myrsinites is one of the oldest spurges described and used in folk medicine. It is characterized by blue-grey stems similar to myrtle, and it is spread in the Mediterranean region, Asia, and the USA. Chemical analysis of E. myrsinites collected in Turkey afforded the isolation of 4 diterpenes based on the so-called myrsinane skeleton being tetraesters of the tetracyclic diterpene alcohol myrsinol. In this study, the phytochemical analysis of this species collected in Italy has been undertaken to afford the isolation of a new atisane diterpene, named myrsatisane, 3 ingenol derivatives, along with the 4 tetraester derivatives previously found. A triterpene compound based on the euphane skeleton has also been isolated. Structural elucidation of the new myrsatisane was based on spectroscopic techniques, including HR-MS and 1- and 2-dimensional NMR experiments. Its relative configuration was determined by NOE correlations, while absolute stereochemistry was obtained by quantum-mechanical DFT studies. While diterpenes with the atisane skeleton are relatively common in Euphorbia species, this is the first report of an atisane diterpene from E. myrsinites. All the isolated terpenes were tested for anti-inflammatory activity on J774A.1 macrophages stimulated with lipopolysaccharide by evaluation of nitrite and pro-inflammatory cytokine Il-1β levels. Among tested compounds, the 3 ingenol diterpenes exhibited a dose-dependent (0.001 – 3 µM) significant activity, thus showing their potential as anti-inflammatory drug candidates.

Key words

Euphorbiaceae - Euphorbia myrsinites - diterpenes - ent-atisane - anti-inflammatory - J774A.1 macrophages

^# Dedicated to Professor Arnold Vlietinck on the occasion of his 80th birthday.

Publication History

Received: 31 January 2021

Accepted after revision: 07 April 2021

Article published online:
27 April 2021

• References

• 1 Turner R. Euphorbias. A Gardenersʼ Guide. London: B.T. Batsford Ltd.; 1995
• 2 Mattioli PA. I Discorsi nei sei libri di Pedacio Dioscoride Anazarbeo nella Materia Medicinale, Vol. III. Venezia: Valgrisi; 1568: 80
• 3 Vasas A, Hohmann J. Euphorbia diterpenes: isolation, structure, biological activity, and synthesis (2008–2012). Chem Rev 2014; 114: 8579-8612
• 4 Corea G, Fattorusso E, Lanzotti V, Motti R, Simon PN, Dumontet C, Di Pietro A. Structure-activity relationships for euphocharacins A–L, a new series of jatrophane diterpenes, as inhibitors of cancer cell P-glycoprotein. Planta Med 2004; 70: 657-665
• 5 Lanzotti V, Barile E, Scambia G, Ferlini C. Cyparissins A and B, jatrophane diterpenes from Euphorbia cyparissias as Pgp inhibitors and cytotoxic agents against ovarian cancer cell lines. Fitoterapia 2015; 104: 75-79
• 6 Corea G, Fattorusso E, Lanzotti V, Taglialatela-Scafati O, Appendino G, Ballero M, Simon PN, Dumontet C, Di Pietro A. Modified jatrophane diterpenes as modulators of multidrug resistance from Euphorbia dendroides L. Bioorg Med Chem 2003; 11: 5221-5227
• 7 Barile E, Fattorusso E, Ialenti A, Ianaro A, Lanzotti V. Paraliane and pepluane diterpenes as anti-inflammatory agents: first insights in structure-activity relationships. Bioorg Med Chem Lett 2007; 17: 4196-4200
• 8 Barile E, Lanzotti V. Biogenetical related highly oxygenated macrocyclic diterpenes from sea spurge Euphorbia paralias . Org Lett 2007; 9: 3603-3606
• 9 Yazdiniapour Z, Ghanadian M, Zolfaghari B, Lanzotti V. 6 (17)-Epoxylathyrane diterpenes from Euphorbia sogdiana Popov with cytotoxic activity. Fitoterapia 2016; 108: 87-92
• 10 Öksüz S, Gürek F, Gil RR, Pengsuparp T, Pezzuto JM, Cordell GA. Four diterpene esters from Euphorbia myrsinites . Phytochemistry 1995; 38: 1457-1462
• 11 Wang LY, Wang NL, Yao XS, Miyata S, Kitanaka S. Diterpenes from the roots of Euphorbia kansui and their in vitro effects on the cell division of Xenopus (2). Chem Pharm Bull 2003; 51: 935-941
• 12 Leong YW, Harrison LJ. (20R,23E)-Eupha-8,23-diene-3β,25-diol from Tripetalum cymosum . Phytochemistry 1999; 50: 849-857
• 13 Halder N, Robien W. CSEARCH-Robot-Referee. Accessed March 17, 2021 at: http://nmrpredict.orc.univie.ac.at/c13robot/robot.php
• 14 Moosmann P, Ueoka R, Grauso L, Mangoni A, Morinaka BI, Guggel M, Piel J. Cyanobacterial ent-sterol-like natural products from a deviated ubiquinone pathway. Angew Chem Int Ed Engl 2017; 56: 4987-4990
• 15 Grauso L, Li Y, Scarpato S, Shulha O, Rárová L, Strnad M, Teta R, Mangoni A, Zidorn C. Structure and conformation of zosteraphenols, tetracyclic diarylheptanoids from the seagrass Zostera marina: an NMR and DFT study. Org Lett 2020; 22: 78-82
• 16 Teta R, Sala GD, Esposito G, Via C, Mazzoccoli C, Piccoli C, Bertin M, Costantino V, Mangoni A. A joint molecular networking study of a Smenospongia sponge and a cyanobacterial bloom revealed new antiproliferative chlorinated polyketides. Org Chem Front 2019; 6: 1762-1774
• 17 Grauso L, Teta R, Esposito G, Menna M, Mangoni A. Computational prediction of chiroptical properties in structure elucidation of natural products. Nat Prod Rep 2019; 36: 1005-1030
• 18 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich A, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery jr. JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ. Gaussian 16, Revision A.03. Wallingford, CT: Gaussian Inc.; 2016
• 19 Lodewyk MW, Siebert MR, Tantillo DJ. Computational prediction of 1H and 13C chemical shifts: a useful tool for natural product, mechanistic, and synthetic organic chemistry. Chem Rev 2012; 112: 1839-1862