Terpenoids from the Oleo-Gum-Resin of Boswellia serrata and Their Antiplasmodial Effects In Vitro

Abstract

In the course of our ongoing search for new natural products as leads against protozoal diseases, the dichloromethane extract of Indian frankincense, the oleo-gum-resin obtained from Boswellia serrata, showed in vitro activity against Plasmodium falciparum. Bioactivity-guided fractionation led to the isolation of eight diterpenes: (1S,3E,7E,11R)-verticilla-3,7,12(18)-triene (1), cembrene A (2), serratol (3), 1S,3E,7R,8R,11E-7,8-epoxy-cembra-3,11-dien-1-ol (4), incensole oxide (5), rel (1S,3R,7E,11S,12R)-1,12-epoxy-4-methylenecembr-7-ene-3, 11-diol (6), isoincensole oxide (7), and isodecaryiol (8). Furthermore, 10 triterpenes, namely, oleanolic acid (9), 11-keto-β-boswellic acid (10), 3-epi-neoilexonol (11), uvaol (12), β-boswellic aldehyde (13), 5α-tirucalla-8,24-dien-3α-ol (14), isoflindissone lactone (15), isoflindissol lactone (16), rel (8R,9S,20R)-tirucall-24-ene-3β,20-diol (17), and rel (3α,8R, 9S,20R,24S)-20,24-epoxytirucalla-3,25-diol (18) as well as the sesquiterpene β-bourbonene (19), the monoterpene carvacrol (20) and the phenyl propanoids methyleugenol (21), and p-methoxycinnamaldehyde (22) were isolated. All compounds were identified by mass spectrometry and nuclear magnetic resonance spectroscopic measurements. Compounds 6, 11, and 16–18 are described for the first time. Compounds 13 – 15 are isolated as natural products for the first time, compound 8 for the first time from a plant. Antiplasmodial IC₅₀ values and cytotoxicity against L6 rat skeletal myoblasts were determined. Isoflindissone lactone (15) was the most active compound with an IC₅₀ of 2.2 µM against P. falciparum and a selectivity index of 18.

Key words

Boswellia serrata - Plasmodium falciparum - antiprotozoal activity - Burseraceae - diterpenes - triterpenes

• References

• 1 WHO. Fact sheet: Malaria. Available at. http://www.who.int/mediacentre/factsheets/fs094/en/ Accessed March 20, 2017
• 2 Schmidt TJ, Khalid SA, Romanha AJ, Alves T, Biavatti MW, Brun R, Da Costa FB, de Castro SL, Ferreira VF, de Lacerda M, Lago J, Leon LL, Lopes NP, das Neves Amorim RC, Niehues M, Ogungbe IV, Pohlit AM, Scotti MT, Setzer WN, de Soeiro MNC, Steindel M, Tempone A. The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases – Part I. Curr Med Chem 2012; 19: 2128-2175
• 3 Schmidt TJ, Khalid SA, Romanha AJ, Alves T, Biavatti MW, Brun R, Da Costa FB, de Castro SL, Ferreira VF, de Lacerda M, Lago J, Leon LL, Lopes NP, das Neves Amorim RC, Niehues M, Ogungbe IV, Pohlit AM, Scotti MT, Setzer WN, de Soeiro MNC, Steindel M, Tempone AG. The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases – Part II. Curr Med Chem 2012; 19: 2176-2228
• 4 Bansal N, Mehan S, Kalra S, Khanna D. Boswellia serrata – frankincense (A Jesus gifted herb); an updated pharmacological profile. Pharmacologia 2013; 4: 457-463
• 5 Schmidt TJ, Kaiser M, Brun R. Complete structural assignment of serratol, a cembrane-type diterpene from Boswellia serrata, and evaluation of its antiprotozoal activity. Planta Med 2011; 77: 849-850
• 6 Hernández-Hernández JD, Román-Marín LU, Cerda-García-Rojas CM, Joseph-Nathan P. Verticillane derivatives from Bursera suntui and Bursera kerberi . J Nat Prod 2005; 68: 1598-1602
• 7 Bai S, Jain M. 1H and 13C assignments of five cembrenes from guggul. Magn Reson Chem 2008; 46: 791-793
• 8 Hernandez-Hernandez JD, Garcia-Gutierrez HA, Roman-Marin LU, Torres-Blanco YI, Cerda-Garcia-Rojas CM, Joseph-Nathan P. Absolute configuration of cembrane diterpenoids from Bursera multijuga . NPC 2014; 9: 1249-1252
• 9 Ren J, Wang Y, Wang A, Wu L, Zhang H, Wang W, Su Y, Qin H. Cembranoids from the gum resin of Boswellia carterii as potential antiulcerative colitis agents. J Nat Prod 2015; 78: 2322-2331
• 10 Forcellese ML, Nicoletti R, Petrossi U. The structure of isoincensole-oxide. Tetrahedron 1972; 28: 325-331
• 11 Gács-Baitz E, Radics L, Fardella G, Corsano S. 13C NMR study of some 14-membered macrocyclic diterpenes. J Chem Research (M) 1978; 1701-1713
• 12 Kato T, Yen CC, Uyehara T, Kitahara Y. Cyclization of polyenes XXIII. Synthesis and stereochemistry of isoincensole-oxide. Chem Lett 1977; 6: 565-568
• 13 Boscarelli A, Giglio E, Quagliata C. Structure and conformation of incensole oxide. Acta Crystallogr B 1981; 37: 744-746
• 14 Rahelivao MP, Gruner M, Lubken T, Islamov D, Kataeva O, Andriamanantoanina H, Bauer I, Knölker H. Chemical constituents of the soft corals Sinularia vanderlandi and Sinularia gravis from the coast of Madagascar. Org Biomol Chem 2016; 14: 989-1001
• 15 Yasumoto M, Mada K, Ooi T, Kusumi T. New terpenoid components from the volatile oils of the soft corals Clavularia viridis and Sarcophyton acutangulum . J Nat Prod 2000; 63: 1534-1536
• 16 Zhang Y, Jayaprakasam B, Seeram NP, Olson LK, DeWitt D, Nair MG. Insulin secretion and cyclooxygenase enzyme inhibition by cabernet sauvignon grape skin compounds. J Agric Food Chem 2004; 52: 228-233
• 17 Jauch J, Bergmann J. An efficient method for the large-scale preparation of 3-O-acetyl-11-oxo-β-boswellic acid and other boswellic acids. Eur J Org Chem 2003; 24: 4752-4756
• 18 Mahato SB, Kundu AP. 13C NMR Spectra of pentacyclic triterpenoids – a compilation and some salient features. Phytochemistry 1994; 37: 1517-1575
• 19 Matsunaga S, Tanaka R, Akagi M. Triterpenoids from Euphorbia maculata . Phytochemistry 1988; 27: 535-537
• 20 Siddiqui S, Hafeez F, Begum S, Siddiqui BS. Kaneric acid, a new triterpene from the leaves of Nerium oleander . J Nat Prod 1986; 49: 1086-1090
• 21 El-Seedi HR. Antimicrobial triterpenes from Poulsenia armata Miq. Standl. Nat Prod Res 2005; 19: 197-202
• 22 Lemes GdF, Ferri PH, Lopes MN. Constituintes químicos de Hyptidendron canum (Pohl ex Benth.) R. Harley (Lamiaceae). Quím Nova 2011; 34: 39-42
• 23 Wang F, Li Z, Cui H, Hua H, Jing Y, Liang S. Two new triterpenoids from the resin of Boswellia carterii . J Asian Nat Prod Res 2011; 13: 193-197
• 24 Fetizon M, Moreau G, Moreau N. Détermination de la conformation dʼaldéhydes en position 4β, en série di- ou triterpenique. Bull Soc Chim Fr 1968; 8: 3295-3301
• 25 Bartlett WR, Johnson WS, Plummer MS, Small VR. Biomimetic polyene cyclizations. Cationic cyclization of a substrate having an internal acetylenic bond. Synthesis of euphol and tirucallol. J Org Chem 1990; 55: 2215-2224
• 26 Zhang P, Jin Y, Chen J, Yao H, Zhang H, Yu A, Li X. Ultrasonic-assisted nebulization extraction coupled with SPE and HPLC for the determination of triterpenoids in root of Euphorbia pekinensis Rupr. Chromatographia 2013; 76: 967-974
• 27 Boar RB, Couchman LA, Perkins MJ. Synthesis of some 3-oxygenated 5α-tirucalla-7, 24- and -8,24-dienes. J Chem Research (M) 1982; 1052-1063
• 28 Kolossváry I, Guida WC. Low mode search. An efficient, automated computational method for conformational analysis: application to cyclic and acyclic alkanes and cyclic peptides. J Am Chem Soc 1996; 118: 5011-5019
• 29 Halgren TA. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem 1996; 17: 490-519
• 30 Paul M, Brüning G, Bergmann J, Jauch J. A thin-layer chromatography method for the identification of three different olibanum resins (Boswellia serrata, Boswellia papyrifera and Boswellia carterii, respectively, Boswellia sacra). PCA 2012; 23: 184-189
• 31 Guang-Yi L, Gray AL, Waterman PG. Tirucallane and oleanane triterpenes from the resin of Aucoumea klaineana . Phytochemistry 1988; 27: 2283-2286
• 32 Birch AJ, Collins DJ, Muhammad S, Turnbull JP. 513. The structure of flindissol. Some remarks on the elemi acids. J Chem Soc (R) 1963; 2762-2772
• 33 Kim KH, Choi SU, Kim YC, Lee KR. Tirucallane triterpenoids from Cornus walteri . J Nat Prod 2011; 74: 54-59
• 34 Mishra M, Shukla YN, Kumar S. Euphane triterpenoid and lipid constituents from Butea monosperma . Phytochemistry 2000; 54: 835-838
• 35 Sandra P, Medvedovici A, Zhao Y, David F. Characterization of triglycerides in vegetable oils by silver-ion packed-column supercritical fluid chromatography coupled to mass spectroscopy with atmospheric pressure chemical ionization and coordination ion spray. J Chrom A 2002; 974: 231-241
• 36 Tomioka K, Tanaka M, Koga K. Stereoselective reactions. XVI. Total synthesis of (−)-β-bourbonene by employing asymmetric (2 + 2) photocycloaddition reaction of chiral butenolide. Chem Pharm Bull 1989; 37: 1201-1207
• 37 Gozzi C, Convard A, Husset M. Heterogeneous acid-catalysed isomerization of carvone to carvacrol. React Kinet Catal Lett 2009; 97: 301-306
• 38 Meepagala KM, Sturtz G, Wedge DE. Antifungal constituents of the essential oil fraction of Artemisia dracunculus L. var. dracunculus . J Agric Food Chem 2002; 50: 6989-6992
• 39 Su B, Takaishi Y. Morinins LP, Five new phenylpropanol derivatives from Morina chinensis . Chem Pharm Bull 1999; 47: 1569-1572
• 40 Cimanga RK, Tona GL, Mesia GK, Kambu OK, Bakana DP, Kalenda PD, Penge AO, Muyembe JT, Totté J, Pieters L, Vlietinck AJ. Bioassay-guided isolation of antimalarial triterpenoid acids from the leaves of Morinda lucida . Pharm Biol 2008; 44: 677-681
• 41 Steele JCP, Warhurst DC, Kirby GC, Simmonds MSJ. In vitro and in vivo evaluation of betulinic acid as an antimalarial. PTR 1999; 13: 115-119
• 42 Llurba Montesino N, Kaiser M, Brun R, Schmidt TJ. Search for antiprotozoal activity in herbal medicinal preparations; new natural leads against neglected tropical diseases. Molecules 2015; 20: 14118-14138
• 43 Molecular Operating Environment (MOE), 2016.08. Montreal: Chemical Computing Group Inc.; 2017
• 44 Nour AMM, Khalid SA, Kaiser M, Brun R, Abdallah WE, Schmidt TJ. The antiprotozoal activity of sixteen asteraceae species native to Sudan and bioactivity-guided isolation of xanthanolides from Xanthium brasilicum . Planta Med 2009; 75: 1363-1368
• 45 Huber W, Koella JC. A comparison of three methods of estimating EC₅₀ in studies of drug resistance of malaria parasites. Acta Trop 1993; 55: 257-261