Effects of Enantiomerically Pure β-Carboline Alkaloids from Picrasma quassioides on Human Hepatoma Cells

Abstract

Four pairs of β-carboline enantiomers (1a/1b–4a/4b), 2 β-carboline derivatives (5 – 6) with a single enantiomeric configuration, together with 2 known achiral congeners (7 – 8) were isolated from the stems of Picrasma quassioides. Their structures were elucidated on the basis of extensive spectroscopic analyses and quantum mechanical calculations. Compound 5 possesses a 4,5-seco β-carboline framework and represents the first example of this type of β-carboline alkaloids from nature. A possible biosynthetic pathway is proposed to generate the racemate 4 and the enantiomerically pure compounds 5 and 6. All isolates were screened for their cytotoxicity against hepatocellular carcinoma Hep3B and HepG2 cells, which revealed that enantiomeric compounds 4a and 4b had distinctive effects in HepG2 cells. Further investigation showed that 4b could induce apoptosis in HepG2 cells.

Key words

Picrasma quassioides - Simaroubaceae - β-carboline alkaloids - biosynthesis - cytotoxicity - enantioselectivity

• References

• 1 Chen SK, Chen BY. Chinese Flora. Beijing: Science Press; 1997
• 2 Xuan YH, Jin Y, Row KH, Jin YS. Antioxidant and anticancer activities of extracts from Picrasma quassioides (D. Don) Benn. Asian J Chem 2010; 22: 7219-7226
• 3 Lee HE, Choi ES, Shin JA, Kim LH, Cho NP, Cho SD. Apoptotic effect of methanol extract of Picrasma quassioides by regulating specificity protein 1 in human cervical cancer cells. Cell Biochem Funct 2014; 32: 229-235
• 4 Koike K, Ohmoto T, Higuchi T. The alkaloids of Picrasma quassioides. Part 10. Picrasidine T, a dimeric β-carboline alkaloid from Picrasma quassioides . Phytochemistry 1987; 26: 3375-3377
• 5 Jiao W, Gao H, Zhao F, Lin H, Pan Y, Zhou G, Yao X. Anti-inflammatory alkaloids from the stems of Picrasma quassioides Bennet. Chem Pharm Bull 2011; 59: 359-364
• 6 Xu J, Xiao D, Song W, Chen L, Liu W, Xie N, Feng F, Qu W. Quassinoids from the stems of Picrasma quassioides and their cytotoxic and NO production-inhibitory activities. Fitoterapia 2016; 110: 13-19
• 7 Jiao W, Gao H, Zhao F, He F, Zhou G, Yao X. A new neolignan and a new sesterterpenoid from the stems of Picrasma quassioides Bennet. Chem Biodiversity 2011; 8: 1163-1169
• 8 Xu J, Xiao D, Lin Q, He J, Liu W, Xie N, Feng F, Qu W. Cytotoxic tirucallane and apotirucallane triterpenoids from the stems of Picrasma quassioides . J Nat Prod 2016; 79: 1899-1910
• 9 Gong G, Lin Q, Xu J, Ye F, Jiang L, Liu W, He MF, Feng F, Qu W, Xie N. In vivo SAR and STR analyses of alkaloids from Picrasma quassioides identify 1-hydroxymethyl-8-hydroxy-β-carboline as a novel natural angiogenesis inhibitor. RSC Adv 2016; 6: 9484-9494
• 10 Shi Y, Liu X, Fredimoses M, Song M, Chen H, Liu K, Lee MH, Dong Z. FGFR2 regulation by picrasidine Q inhibits the cell growth and induces apoptosis in esophageal squamous cell carcinoma. J Cell Biochem 2017; 119: 2231-2239
• 11 Zhao WY, Shang XY, Zhao L, Yao GD, Sun Z, Huang XX, Song SJ. Bioactivity-guided isolation of β-carboline alkaloids with potential anti-hepatoma effect from Picrasma quassioides (D. Don) Benn. Fitoterapia 2018; 130: 66-72
• 12 Kumar K, Wang P, Sanchez R, Swartz EA, Stewart AF, DeVita RJ. Development of kinase-selective, harmine-based DYRK1A inhibitors that induce pancreatic human β-cell proliferation. J Med Chem 2018; 61: 7687-7699
• 13 Cao R, Peng W, Wang Z, Xu A. Beta-carboline alkaloids: biochemical and pharmacological functions. Curr Med Chem 2007; 14: 497-500
• 14 Jiao W, Gao H, Li C, Zhao F, Jiang R, Wang Y, Zhou G, Yao X. Quassidines AD, Bis-β-carboline alkaloids from the stems of Picrasma quassioides . J Nat Prod 2010; 73: 167-171
• 15 Jiao W, Gao H, Li C, Zhou G, Kitanaka S, Ohmura A, Yao X. β-Carboline alkaloids from the stems of Picrasma quassioides . Magn Reson Chem 2010; 48: 490-495
• 16 Das P, Babbar P, Malhotra N, Sharma M, Jachak GR, Gonnade RG, Shanmugam D, Harlos K, Yogavel M, Sharma A, Reddy DS. Specific stereoisomeric conformations determine the drug potency of cladosporin scaffold against malarial parasite. J Med Chem 2018; 61: 5664-5678
• 17 Fitch RW, Snider BB, Zhou Q, Foxman BM, Pandya AA, Yakel JL, Olson TT, Al-Muhtasib N, Xiao Y, Welch KD, Panter KE. Absolute configuration and pharmacology of the poison frog alkaloid phantasmidine. J Nat Prod 2018; 81: 1029-1035
• 18 Takasu K, Shimogama T, Saiin C, Kim HS, Wataya Y, Brun R, Ihara M. Synthesis and evaluation of β-carbolinium cations as new antimalarial agents based on π-delocalized lipophilic cation (DLC) hypothesis. Chem Pharm Bull 2005; 53: 653-661
• 19 Li HY, Koike K, Ohmoto T. New alkaloids, picrasidines W, X and Y, from Picrasma quassioides and x-ray crystallographic analysis of picrasidine Q. Chem Pharm Bull 1993; 41: 1807-1811
• 20 da Silva WA, Rodrigues jr. MT, Shankaraiah N, Ferreira RB, Andrade CKZ, Pilli RA, Santos LS. Novel supramolecular palladium catalyst for the asymmetric reduction of imines in aqueous media. Org Lett 2009; 11: 3238-3241
• 21 Ohmoto T, Koike K. Studies on the constituents of Picrasma quassioides Bennet. III. The alkaloidal constituents. Chem Pharm Bull 1984; 32: 3579-3583
• 22 Ohmoto T, Koike K. Studies on the alkaloids from Picrasma quassioides Bennet. V. Structures of picrasidines L, M, and P. Chem Pharm Bull 1985; 33: 3847-3851
• 23 Dewick PM. Medicinal natural Products: A biosynthetic Approach. Chichester: John Wiley & Sons; 2002
• 24 Ohmoto T, Koike K. Studies on the constituents of Picrasma quassioides Bennet. II. On the alkaloidal constituents. Chem Pharm Bull 1983; 31: 3198-3204
• 25 Crespi-Perellino N, Guicciardi A, Malyszko G, Minghetti A. Biosynthetic relationship between indole alkaloids produced by cell cultures of Ailanthus altissima . J Nat Prod 1986; 49: 814-822
• 26 Aragozzini F, Maconi E, Gualandris R. Evidence for involvement of ketoglutarate in the biosynthesis of canthin-6-one from cell cultures of Ailanthus altissima . Plant Cell Rep 1988; 7: 213-215
• 27 Stewart ZA, Westfall MD, Pietenpol JA. Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci 2003; 24: 139-145
• 28 Khan FA, Maalik A, Iqbal Z, Malik I. Recent pharmacological developments in β-carboline alkaloid “harmaline”. Eur J Pharmacol 2013; 721: 391-394
• 29 Lunagariya NA, Gohil VM, Kushwah V, Neelagiri S, Jain S, Singh S, Bhutani KK. Design, synthesis and biological evaluation of 1,3,6-trisubstituted β-carboline derivatives for cytotoxic and anti-leishmanial potential. Biorg Med Chem Lett 2016; 26: 789-794
• 30 Liew LPP, Fleming JM, Longeon A, Mouray E, Florent I, Bourguet-Kondracki ML, Copp BR. Synthesis of 1-indolyl substituted β-carboline natural products and discovery of antimalarial and cytotoxic activities. Tetrahedron 2014; 70: 4910-4920
• 31 Wu J, Li C, Zhao M, Wang W, Wang Y, Peng S. A class of novel carboline intercalators: their synthesis, in vitro anti-proliferation, in vivo anti-tumor action, and 3D QSAR analysis. Biorg Med Chem 2010; 18: 6220-6229
• 32 Guo L, Chen W, Cao R, Fan W, Ma Q, Zhang J, Dai B. Synthesis and structure-activity relationships of asymmetric dimeric β-carboline derivatives as potential antitumor agents. Eur J Med Chem 2018; 147: 253-265
• 33 Jagannadh B, Reddy SS, Thangavelu RP. Conformational preferences of 1,4,7-trithiacyclononane: a molecular mechanics and density functional theory study. J Mol Model 2004; 10: 55-59
• 34 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 09. A.01 ed. Wallingford: Gaussian, Inc.; 2016