New Phenylethanoid Glycosides from Cistanche phelypaea and Their Activity as Inhibitors of Monoacylglycerol Lipase (MAGL)

Abstract

Four new phenylethanoid glycosides (1–4), 1-β-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-β-d-glucopyranoside (1), 1-β-p-hydroxyphenyl-ethyl-3,6-O-di-α-l-rhamnopyranosyl-β-d-glucopyranoside (2), 1-β-p-hydroxyphenyl-ethyl-2-O-acetyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-β-d-glucopyranoside (3), and 1-β-p-hydroxyphenyl-ethyl-3,6-di-α-l-rhamnopyranosyl-4-p-coumaroyl-β-d-glucopyranoside (4), together with three known compounds, were isolated from the n-butanol extract of Cistanche phelypaea aerial parts. The structural characterization of all compounds was performed by spectroscopic analyses, including 1D and 2D NMR, and HRESIMS experiments. The isolated compounds were assayed for their inhibitory activity on two enzymes involved in the peculiar glycolytic or lipidic metabolism of cancer cells, human lactate dehydrogenase (LDH), and monoacylglycerol lipase (MAGL), respectively. All the compounds showed negligible activity on LDH, whereas some of them displayed a certain inhibition activity on MAGL. In particular, compound 1 was the most active on MAGL, showing an IC₅₀ value of 88.0 µM, and modeling studies rationalized the supposed binding mode of 1 in the MAGL active site.

Key words

Cistanche phelypaea - Orobanchaceae - phenylethanoid glycosides - cancer - monoacylglycerol lipase - lactate dehydrogenase

• References

• 1 Fahmy GM, El-Tantawi H, Abd El-Ghani MM. Distribution, host range and biomass of two species of Cistanche and Orobanche cernua parasitizing the roots of some Egyptian xerophytes. J Arid Environ 1996; 34: 263-276
• 2 Wang LI, Ding H, Yu HS, Han LF, Lai QH, Zhang LJ, Song XB. Cistanche herba: chemical constituents and pharmacological effects. Chin Herb Med 2015; 7: 135-142
• 3 Xiong Q, Kadota S, Tani T, Namba T. Antioxidative effects of phenylethanoids from Cistanche deserticola . Biol Pharm Bull 1996; 19: 1580-1585
• 4 Morikawa T, Pan Y, Ninomiya K, Imura K, Yuan D, Yoshikawa M, Hayakawa T, Muraoka O. Iridoid and acyclic monoterpene glycosides, kankanosides L, M, N, O, and P from Cistanche tubulosa . Chem Pharma Bull 2010; 58: 1403-1410
• 5 Liu XM, Li J, Jiang Y, Zhao MB, Tu PF. Chemical constituents from Cistanche sinesis (Orobanchaceae). Biochem Syst Ecol 2013; 47: 21-24
• 6 Boulous L. Medicinal Plants of North Africa. Michigan: Reference Publication Algonc; 1983: 286
• 7 Melek FR, El-Shabrawy OA, El-Gindy M, Miyase T, Hilal SH. Pharmacological activity and composition of the ethyl acetate extract of Cistanche phelypaea . Fitoterapia 1993; 64: 11-14
• 8 Deyama T, Yahikozawa K, Al-Easa HS, Rizk AM. Constituents of plants growing in Qatar: part XXXVIII. Constituents of Cistanche phelypaea . Qatar University Sci J 1995; 15: 51-55
• 9 Bader A, Tuccinardi T, Granchi C, Martinelli A, Macchia M, Minutolo F, De Tommasi N, Braca A. Phenylpropanoids and flavonoids from Phlomis kurdica as inhibitors of human lactate dehydrogenase. Phytochemistry 2015; 116: 262-268
• 10 De Leo M, Peruzzi L, Granchi C, Tuccinardi T, Minutolo F, De Tommasi N, Braca A. Constituents of Polygala flavescens ssp. flavescens and their activity as inhibitors of human lactate dehydrogenase. J Nat Prod 2017; 80: 2077-2087
• 11 Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 2008; 18: 54-61
• 12 Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 2010; 140: 49-61
• 13 Fiume L, Manerba M, Vettraino M, Di Stefano G. Inhibition of lactate dehydrogenase activity as an approach to cancer therapy. Future Med Chem 2014; 6: 429-445
• 14 Nomura DK, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, Hoover HH, Cravatt BF. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol 2011; 18: 846-856
• 15 Granchi C, Roy S, Del Fiandra C, Tuccinardi T, Lanza M, Betti L, Giannaccini G, Lucacchini A, Martinelli A, Macchia M, Minutolo F. Triazole-substituted N-hydroxyindol-2-carboxylates as inhibitors of isoform 5 of human lactate dehydrogenase (hLDH5). Medchemcomm 2011; 2: 638-643
• 16 Purkey HE, Robarge K, Chen J, Chen Z, Corson LB, Ding CZ, DiPasquale AG, Dragovich PS, Eigenbrot C, Evangelista M, Fauber BP, Gao Z, Ge H, Hitz A, Ho Q, Labadie SS, Lai KW, Liu W, Liu Y, Li C, Ma S, Malek S, OʼBrien T, Pang J, Peterson D, Salphati L, Sideris S, Ultsch M, Wei B, Yen I, Yue Q, Zhang H, Zhou A. Cell active hydroxylactam inhibitors of human lactate dehydrogenase with oral bioavailability in mice. ACS Med Chem Lett 2016; 7: 896-901
• 17 Tuccinardi T, Granchi C, Rizzolio F, Caligiuri I, Battistello V, Toffoli G, Minutolo F, Macchia M, Martinelli A. Identification and characterization of a new reversible MAGL inhibitor. Bioorg Med Chem 2014; 22: 3285-3291
• 18 Hernández-Torres G, Cipriano M, Hedén E, Björklund E, Canales Á, Zian D, Feliú A, Mecha M, Guaza C, Fowler CJ, Ortega-Gutiérrez S, López-Rodríguez ML. A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. Angew Chem Int Ed Engl 2014; 53: 13765-13770
• 19 He ZD, Yang CR. Brandioside, a phenylpropanoid glycoside from Brandisia hancei . Phytochemistry 1991; 30: 701-706
• 20 Casabuono AC, Pomillo AB. Lignans and a stilbene from Festuca argentina . Phytochemistry 1994; 35: 479-483
• 21 Flamini G, Antognoli E, Marelli I. Two flavonoids and other compounds from aerial parts of Centaurea bracteata from Italy. Phytochemistry 2001; 57: 559-564
• 22 Manerba M, Vettraino M, Fiume L, Di Stefano G, Sartini A, Giacomini E, Buonfiglio R, Roberti M, Recanatini M. Galloflavin (CAS 568-80-9): a novel inhibitor of lactate dehydrogenase. ChemMedChem 2012; 7: 311-317
• 23 Scalvini L, Piomelli D, Mor M. Monoglyceride lipase: structure and inhibitors. Chem Phys Lipids 2016; 197: 13-24
• 24 Kobayashi H, Karasawa H, Miyase T, Fukushima S. Studies on the constituents of Cistanchis herba. III. Isolation and structures of new phenylpropanoid glycosides, cistanosides A and B. Chem Pharm Bull 1984; 32: 3009-3014
• 25 Yoshizawa F, Deyama T, Takizawa N. The constituents of Cistanche tubulosa (SCHRENK) HOOK. f. II.: isolation and structures of a new phenylethanoid glycoside and a new neolignan glycoside. Chem Pharm Bull 1990; 38: 1927-1930
• 26 Milella L, Milazzo S, De Leo M, Vera Saltos MB, Faraone I, Tuccinardi T, Lapillo M, De Tommasi N, Braca A. α-Glucosidase and α-amylase inhibitors from Arcytophyllum thymifolium . J Nat Prod 2016; 79: 2104-2112
• 27 Granchi C, Caligiuri I, Bertelli E, Poli G, Rizzolio F, Macchia M, Martinelli A, Minutolo F, Tuccinardi T. Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors. J Enzyme Inhib Med Chem 2017; 32: 1240-1252
• 28 Schalk-Hihi C, Schubert C, Alexander R, Bayoumy S, Clemente JC, Deckman I, DesJarlais RL, Dzordzorme KC, Flores CM, Grasberger B, Kranz JK, Lewandowski F, Liu L, Ma H, Maguire D, Macielag MJ, McDonnell ME, Mezzasalma Haarlander T, Miller R, Milligan C, Reynolds C, Kuo LC. Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution. Protein Sci 2011; 20: 670-683
• 29 Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The protein data bank. Nucleic Acids Res 2000; 28: 235-242
• 30 Case DA, Berryman JT, Betz RM, Cerutti DS, Cheatham III TE, Darden TA, Duke RE, Giese TJ, Gohlke H, Goetz AW, Homeyer N, Izadi S, Janowski P, Kaus J, Kovalenko A, Lee TS, LeGrand S, Li P, Luchko T, Luo R, Madej B, Merz KM, Monard G, Needham P, Nguyen H, Nguyen HT, Omelyan I, Onufriev A, Roe DR, Roitberg A, Salomon-Ferrer R, Simmerling CL, Smith W, Swails J, Walker RC, Wang J, Wolf RM, Wu X, York DM, Kollman PA. AMBER, version 14. San Francisco, CA: University of California; 2015
• 31 Maestro, version 9.0. Portland, OR: Schrödinger Inc.; 2009
• 32 Macromodel, version 9.7. Portland, OR: Schrödinger Inc.; 2009
• 33 Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19: 1639-1662
• 34 Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2009; 30: 2785-2791