Synthesis and Biological Activity of Embelin and its Derivatives: An Overview

Author(s): Zhaojun Sheng*, Siyuan Ge, Min Gao, Rongchao Jian, Xiaole Chen, Xuetao Xu, Dongli Li, Kun Zhang, Wen-Hua Chen*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 20 , Issue 5 , 2020

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Graphical Abstract:


Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.) of the Myrsinaceae family, and contains two carbonyl groups, a methine group and two hydroxyl groups. With embelin as the lead compound, more than one hundred derivatives have been reported. Embelin is well known for its ability to antagonize the X-linked inhibitor of apoptosis protein (XIAP) with an IC50 value of 4.1 μM. The potential of embelin and its derivatives in the treatment of various cancers has been extensively studied. In addition, these compounds display a variety of other biological effects: antimicrobial, antioxidant, analgesic, anti-inflammatory, anxiolytic and antifertility activity. This paper reviews the recent progress in the synthesis and biological activity of embelin and its derivatives. Their cellular mechanisms of action and prospects in the research and development of new drugs are also discussed.

Keywords: Embelin, anticancer, anti-inflammatory activity, benzoquinone, XIAP antagonist, natural product

Poojari, R. Embelin - A drug of antiquity: Shifting the paradigm towards modern medicine. Expert Opin. Investig. Drugs, 2014, 23(3), 427-444.
[] [PMID: 24397264]
Harish, G.U.; Danapur, V.; Jain, R.; Patell, V.M. Endangered medicinal plant Embelia ribes Burm. f.- a review. Pharmacogn. J., 2012, 4(27), 6-19.
Shuveksh, P.S.; Ahmed, K.; Padhye, S.; Schobert, R.; Biersack, B. Chemical and biological aspects of the natural 1,4-benzoquinone embelin and its (semi-) synthetic derivatives. Curr. Med. Chem., 2017, 24(18), 1998-2009.
[] [PMID: 28093981]
Viault, G.; Grée, D.; Das, S.; Yadav, J.S.; Grée, R. Synthesis of a focused chemical library based on derivatives of embelin, a natural product with proapoptotic and anticancer properties. Eur. J. Org. Chem., 2011, (7), 1233-1241.
Stasiuk, M.; Kozubek, A. Embelin - A promising bioactive compound from the Myrsinaceae family. Glob. J. Biochem., 2011, 2(4), 262-270.
Karpakal, S.; Rajasekharan, P.E. Ethnopharmacological uses of Embelia ribes Burm. f. - a review. J. Pharm. Biol. Sci., 2014, 9(3), 23-30.
Prabhu, K.S.; Achkar, I.W.; Kuttikrishnan, S.; Akhtar, S.; Khan, A.Q.; Siveen, K.S.; Uddin, S. Embelin: A benzoquinone possesses therapeutic potential for the treatment of human cancer. Future Med. Chem., 2018, 10(8), 961-976.
[] [PMID: 29620447]
Feresin, G.E.; Tapia, A.; Sortino, M.; Zacchino, S.; de Arias, A.R.; Inchausti, A.; Yaluff, G.; Rodriguez, J.; Theoduloz, C.; Schmeda-Hirschmann, G. Bioactive alkyl phenols and embelin from Oxalis erythrorhiza. J. Ethnopharmacol., 2003, 88(2-3), 241-247.
[] [PMID: 12963150]
Nikolovska-Coleska, Z.; Xu, L.; Hu, Z.; Tomita, Y.; Li, P.; Roller, P.P.; Wang, R.; Fang, X.; Guo, R.; Zhang, M.; Lippman, M.E.; Yang, D.; Wang, S. Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J. Med. Chem., 2004, 47(10), 2430-2440.
[] [PMID: 15115387]
Deveraux, Q.L.; Reed, J.C. IAP family proteins--suppressors of apoptosis. Genes Dev., 1999, 13(3), 239-252.
[] [PMID: 9990849]
Shi, Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell, 2002, 9(3), 459-470.
[] [PMID: 11931755]
Xu, T.; Li, T.; Zhang, Y.; Huan, S.; Cui, T.; Sun, L. Inhibition of Akt/NF-κB/survivin pathway by embelin on castration-resistant prostate cancer cells. Int. J. Clin. Exp. Med., 2017, 10(3), 4386-4397.
Sumalatha, K.; Gowda, M.; Meenakshisundaram, S. ROS-mediated induction of apoptosis by benzoquinone embelin in human colon adenocarcinoma cells HT-29. J. Complement. Integr. Med., 2017, 14(2) /j/jcim.2017.14.issue-2/jcim-2016-0131/jcim-2016-0131.xml.
[] [PMID: 28306533]
Lee, Y-J.; Park, B-S.; Park, H-R.; Yu, S-B.; Kang, H-M.; Kim, I-R. XIAP inhibitor embelin induces autophagic and apoptotic cell death in human oral squamous cell carcinoma cells. Environ. Toxicol., 2017, 32(11), 2371-2378.
[] [PMID: 28722333]
Lee, H.; Ko, J-H.; Baek, S.H.; Nam, D.; Lee, S.G.; Lee, J.; Yang, W.M.; Um, J-Y.; Kim, S-H.; Shim, B.S.; Ahn, K.S. Embelin inhibits invasion and migration of MDA-MB-231 breast cancer cells by suppression of CXC chemokine receptor 4, matrix metalloproteinases-9/2, and epithelial-mesenchymal transition. Phytother. Res., 2016, 30(6), 1021-1032.
[] [PMID: 27030214]
Fu, X.; Pang, X.; Qi, H.; Chen, S.; Li, Y.; Tan, W. XIAP inhibitor Embelin inhibits bladder cancer survival and invasion in vitro. Clin. Transl. Oncol., 2016, 18(3), 277-282.
[] [PMID: 26209051]
Yang, T.; Lan, J.; Huang, Q.; Chen, X.; Sun, X.; Liu, X.; Yang, P.; Jin, T.; Wang, S.; Mou, X. Embelin sensitizes acute myeloid leukemia cells to TRAIL through XIAP inhibition and NF-κB inactivation. Cell Biochem. Biophys., 2015, 71(1), 291-297.
[] [PMID: 25358405]
Wang, D-G.; Sun, Y-B.; Ye, F.; Li, W.; Kharbuja, P.; Gao, L.; Zhang, D.Y.; Suo, J. Anti-tumor activity of the X-linked inhibitor of apoptosis (XIAP) inhibitor embelin in gastric cancer cells. Mol. Cell. Biochem., 2014, 386(1-2), 143-152.
[] [PMID: 24136460]
Radhakrishnan, N.; Gnanamani, A. 2,5-Dihydroxy-3-undecyl-1,4-benzoquinone (embelin)- a second solid gold of India- A review. Int. J. Pharm. Pharm. Sci., 2014, 6(2), 23-30.
Chepkwony, S.C.; Kiprono, P.; Lutta, S. Structure determination of nickel-embelin complex. IOSR J. Appl. Chem., 2014, 7(7), 21-24.
Aravindhan, R.; Sreelatha, T.; Perumal, P.T.; Gnanamani, A. Synthesis, characterization and biological profile of metal and azo-metal complexes of embelin. Complex Metals, 2014, 1(1), 69-79.
Subramanian, L.; Leema, M.; Pradeep, N.S.; Joy, B.; Pillai, Z.S. Synthesis and antibacterial screening of novel derivatives of embelin. IOP Conf. Series: Mater. Sci. Engineer., 2018.
Peduto, A.; Scuotto, M.; Krauth, V.; Roviezzo, F.; Rossi, A.; Temml, V.; Esposito, V.; Stuppner, H.; Schuster, D.; D’Agostino, B.; Schiraldi, C.; de Rosa, M.; Werz, O.; Filosa, R. Optimization of benzoquinone and hydroquinone derivatives as potent inhibitors of human 5-lipoxygenase. Eur. J. Med. Chem., 2017, 127, 715-726.
[] [PMID: 27836196]
Patange, A.N. Synthesis, characterisations, lipid lowering activity and antibacterial Activities of some benzoyl ester substituted embelin derivatives. Orient. J. Chem., 2017, 33(1), 430-438.
Viault, G.; Babu, K.S.; Gautier, F.; Barillé-Nion, S.; Juin, P.; Tasseau, O.; Grée, R. Hemisynthesis of selected embelin analogs and investigation of their proapoptotic activity against cancer cells. Med. Chem., 2013, 9(8), 1028-1034.
[] [PMID: 23373598]
Bezu, K.; Bisrat, D.; Asres, K. In vivo antimalarial evaluation of embelin and its semi-synthetic aromatic amine derivatives. Pharmacogn. J., 2015, 7(5), 305-310.
Mahendran, S.; Badami, S.; Ravi, S.; Thippeswamy, B.S.; Veerapur, V.P. Synthesis and evaluation of analgesic and anti-inflammatory activities of most active free radical scavenging derivatives of embelin-A structure-activity relationship. Chem. Pharm. Bull. (Tokyo), 2011, 59(8), 913-919.
[] [PMID: 21804233]
Gudala, S.; Sharma, A.; Rao, V.R.; Kumar, A.; Penta, S. Recent developments in synthesis of embelin heterocyclic derivatives and their biological applications. Chem. Pap., 2018, 72(5), 1065-1080.
Peña, R.; Jiménez-Alonso, S.; Feresin, G.; Tapia, A.; Méndez-Alvarez, S.; Machín, F.; Ravelo, A.G.; Estévez-Braun, A. Multicomponent synthesis of antibacterial dihydropyridin and dihydropyran embelin derivatives. J. Org. Chem., 2013, 78(16), 7977-7985.
[] [PMID: 23841668]
Peña, R.; Martín, P.; Feresin, G.E.; Tapia, A.; Machín, F.; Estévez-Braun, A. Domino synthesis of embelin derivatives with antibacterial activity. J. Nat. Prod., 2016, 79(4), 970-977.
[] [PMID: 26924672]
Martín-Acosta, P.; Feresin, G.; Tapia, A.; Estévez-Braun, A. Microwave-assisted organocatalytic intramolecular Knoevenagel/hetero Diels-Alder reaction with O-(arylpropynyloxy)-salicylal-dehydes: Synthesis of polycyclic embelin derivatives. J. Org. Chem., 2016, 81(20), 9738-9756.
[] [PMID: 27680299]
Chen, J.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Wang, S. Design, synthesis, and characterization of new embelin derivatives as potent inhibitors of X-linked inhibitor of apoptosis protein. Bioorg. Med. Chem. Lett., 2006, 16(22), 5805-5808.
[] [PMID: 16962773]
McErlean, C.S.P.; Moody, C.J. First synthesis of N-(3-carboxylpropyl)-5-amino-2-hydroxy-3- tridecyl-1,4-benzoquinone, an unusual quinone isolated from Embelia ribes. J. Org. Chem., 2007, 72(26), 10298-10301.
[] [PMID: 17999537]
Lamblin, M.; Sallustrau, A.; Commandeur, C.; Cresteil, T.; Felpin, F.; Dessolin, J. Synthesis and biological evaluation of hydrophilic embelin derivatives. Tetrahedron, 2012, 68(24), 4655-4663.
Filosa, R.; Peduto, A.; Aparoy, P.; Schaible, A.M.; Luderer, S.; Krauth, V.; Petronzi, C.; Massa, A.; de Rosa, M.; Reddanna, P.; Werz, O. Discovery and biological evaluation of novel 1,4-benzoquinone and related resorcinol derivatives that inhibit 5-lipoxygenase. Eur. J. Med. Chem., 2013, 67, 269-279.
[] [PMID: 23871907]
Kim, J.W.; Inagaki, Y.; Mitsutake, S.; Maezawa, N.; Katsumura, S.; Ryu, Y.W.; Park, C.S.; Taniguchi, M.; Igarashi, Y. Suppression of mast cell degranulation by a novel ceramide kinase inhibitor, the F-12509A olefin isomer K1. Biochim. Biophys. Acta, 2005, 1738(1-3), 82-90.
[] [PMID: 16352467]
Chen, F.; Zhang, G.; Hong, Z.; Lin, Z.; Lei, M.; Huang, M.; Hu, L. Design, synthesis, and SAR of embelin analogues as the inhibitors of PAI-1 (plasminogen activator inhibitor-1). Bioorg. Med. Chem. Lett., 2014, 24(10), 2379-2382.
[] [PMID: 24731276]
Coyle, R.; Slattery, K.; Ennis, L.; O’sullivan, M.J.; Zisterer, D.M. The XIAP inhibitor embelin sensitises malignant rhabdoid tumour cells to TRAIL treatment via enhanced activation of the extrinsic apoptotic pathway. Int. J. Oncol., 2019, 55(1), 191-202.
[] [PMID: 31115498]
Ko, J-H.; Lee, S-G.; Yang, W.M.; Um, J-Y.; Sethi, G.; Mishra, S.; Shanmugam, M.K.; Ahn, K.S. The application of embelin for cancer prevention and therapy. Molecules, 2018, 23(3), 621-634.
[] [PMID: 29522451]
Xu, M.; Cui, J.; Fu, H.; Proksch, P.; Lin, W.; Li, M. Embelin derivatives and their anticancer activity through microtubule disassembly. Planta Med., 2005, 71(10), 944-948.
[] [PMID: 16254827]
Singh, B.; Guru, S.K.; Sharma, R.; Bharate, S.S.; Khan, I.A.; Bhushan, S.; Bharate, S.B.; Vishwakarma, R.A. Synthesis and anti-proliferative activities of new derivatives of embelin. Bioorg. Med. Chem. Lett., 2014, 24(20), 4865-4870.
[] [PMID: 25240254]
Zappavigna, S.; Scuotto, M.; Cossu, A.M.; Ingrosso, D.; De Rosa, M.; Schiraldi, C.; Filosa, R.; Caraglia, M. The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells. J. Exp. Clin. Cancer Res., 2016, 35(1), 167-180.
[] [PMID: 27770821]
Li, S.; Wei, X.; He, J.; Tian, X.; Yuan, S.; Sun, L. Plasminogen activator inhibitor-1 in cancer research. Biomed. Pharmacother., 2018, 105, 83-94.
[] [PMID: 29852393]
Placencio, V.R.; DeClerck, Y.A. Plasminogen activator inhibitor-1 in Cancer: Rationale and insight for future therapeutic testing. Cancer Res., 2015, 75(15), 2969-2974.
[] [PMID: 26180080]
Litchfield, D.W. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem. J., 2003, 369(Pt 1), 1-15.
[] [PMID: 12396231]
Martín-Acosta, P.; Haider, S.; Amesty, Á.; Aichele, D.; Jose, J.; Estévez-Braun, A. A new family of densely functionalized fused-benzoquinones as potent human protein kinase CK2 inhibitors. Eur. J. Med. Chem., 2018, 144, 410-423.
[] [PMID: 29288942]
Sivasankar, C.; Gayathri, S.; Bhaskar, J.P.; Krishnan, V.; Pandian, S.K. Evaluation of selected Indian medicinal plants for antagonistic potential against Malassezia spp. and the synergistic effect of embelin in combination with ketoconazole. Microb. Pathog., 2017, 110, 66-72.
[] [PMID: 28645774]
Mahendran, S.; Badami, S.; Ravi, S.; Thippeswamy, B.S.; Veerapur, V.P. Antioxidant, analgesic and anti-inflammatory properties of new ninhydrin adduct of embelin. Pharm. Chem. J., 2011, 45(9), 547-551.
Thippeswamy, B.S.; Mahendran, S.; Biradar, M.I.; Raj, P.; Srivastava, K.; Badami, S.; Veerapur, V.P. Protective effect of embelin against acetic acid induced ulcerative colitis in rats. Eur. J. Pharmacol., 2011, 654(1), 100-105.
[] [PMID: 21185828]
Kumar, G.K.; Dhamotharan, R.; Kulkarni, N.M.; Honnegowda, S.; Murugesan, S. Embelin ameliorates dextran sodium sulfate-induced colitis in mice. Int. Immunopharmacol., 2011, 11(6), 724-731.
[] [PMID: 21296695]
Kalyan Kumar, G.; Dhamotharan, R.; Kulkarni, N.M.; Mahat, M.Y.A.; Gunasekaran, J.; Ashfaque, M. Embelin reduces cutaneous TNF-α level and ameliorates skin edema in acute and chronic model of skin inflammation in mice. Eur. J. Pharmacol., 2011, 662(1-3), 63-69.
[] [PMID: 21549694]
Schaible, A.M.; Traber, H.; Temml, V.; Noha, S.M.; Filosa, R.; Peduto, A.; Weinigel, C.; Barz, D.; Schuster, D.; Werz, O. Potent inhibition of human 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 by the anti-carcinogenic and anti-inflammatory agent embelin. Biochem. Pharmacol., 2013, 86(4), 476-486.
[] [PMID: 23623753]
Filosa, R.; Peduto, A.; Schaible, A.M.; Krauth, V.; Weinigel, C.; Barz, D.; Petronzi, C.; Bruno, F.; Roviezzo, F.; Spaziano, G.; D’Agostino, B.; De Rosa, M.; Werz, O. Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes. Eur. J. Med. Chem., 2015, 94, 132-139.
[] [PMID: 25765759]
Nidhi, D.A.; Dadwal, A.; Hallan, S.S.; Sharma, S.; Mishra, N. Development of enteric-coated microspheres of embelin for their beneficial pharmacological potential in ulcerative colitis. Artif. Cells Nanomed. Biotechnol., 2017, 45(6), 1-9.
[] [PMID: 27388946]
Yonezawa, T.; Kurata, R.; Yoshida, K.; Murayama, M.A.; Cui, X.; Hasegawa, A. Free fatty acids-sensing G protein-coupled receptors in drug targeting and therapeutics. Curr. Med. Chem., 2013, 20(31), 3855-3871.
[] [PMID: 23862620]
Gaidarov, I.; Anthony, T.; Gatlin, J.; Chen, X.; Mills, D.; Solomon, M.; Han, S.; Semple, G.; Unett, D.J. Embelin and its derivatives unravel the signaling, proinflammatory and antiatherogenic properties of GPR84 receptor. Pharmacol. Res., 2018, 131, 185-198.
[] [PMID: 29471103]
Durg, S.; Veerapur, V.P.; Neelima, S.; Dhadde, S.B. Antidiabetic activity of Embelia ribes, embelin and its derivatives: A systematic review and meta-analysis. Biomed. Pharmacother., 2017, 86, 195-204.
[] [PMID: 27984799]
Alam, M.S.; Ahad, A.; Abidin, L.; Aqil, M.; Mir, S.R.; Mujeeb, M. Embelin-loaded oral niosomes ameliorate streptozotocin-induced diabetes in Wistar rats. Biomed. Pharmacother., 2018, 97, 1514-1520.
[] [PMID: 29793314]
Jain, S.; Jain, A.; Bhargav, S. Formulation and evaluation of embelin loaded pectin nanoparticles for the treatment of diabetes. Pancreatology, 2018, 18(4)(Suppl.), S39.
Halliwell, B. Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet, 1994, 344(8924), 721-724.
[] [PMID: 7915779]
Joshi, R.; Kamat, J.P.; Mukherjee, T. Free radical scavenging reactions and antioxidant activity of embelin: Biochemical and pulse radiolytic studies. Chem. Biol. Interact., 2007, 167(2), 125-134.
[] [PMID: 17379198]
Durg, S. B, N.K.; Vandal, R.; Dhadde, S.B.; Thippeswamy, B.S.; Veerapur, V.P.; Badami, S. Antipsychotic activity of embelin isolated from Embelia ribes: A preliminary study. Biomed. Pharmacother., 2017, 90, 328-331.
[] [PMID: 28376400]
Kundap, U.P.; Bhuvanendran, S.; Kumari, Y.; Othman, I.; Shaikh, M.F. Plant derived phytocompound, embelin in CNS disorders: a systematic review. Front. Pharmacol., 2017, 8, 76.
[] [PMID: 28289385]
Arora, R.; Deshmukh, R. Embelin attenuates intracerebroventricular streptozotocin-induced behavioral, biochemical, and neurochemical abnormalities in Rats. Mol. Neurobiol., 2017, 54(9), 6670-6680.
[] [PMID: 27744573]
Bhuvanendran, S.; Hanapi, N.A.; Ahemad, N.; Othman, I.; Yusof, S.R.; Shaikh, M.F. Embelin, a potent molecule for Alzheimer’s disease: a proof of concept rrom blood-brain barrier permeability, acetylcholinesterase inhibition and molecular docking studies. Front. Neurosci., 2019, 13, 495-495.
[] [PMID: 31156375]
Nuthakki, V.K.; Sharma, A.; Kumar, A.; Bharate, S.B. Identification of embelin, a 3-undecyl-1,4-benzoquinone from Embelia ribes as a multitargeted anti-Alzheimer agent. Drug Dev. Res., 2019, 1-11.
[] [PMID: 31050027]
Kundap, U.P.; Paudel, Y.N.; Kumari, Y.; Othman, I.; Shaikh, M.F. Embelin prevents seizure and associated cognitive impairments in a pentylenetetrazole-induced kindling zebrafish model. Front. Pharmacol., 2019, 10, 315.
[] [PMID: 31057394]
Singh, I.P.; Bharate, S.B.; Singh, A.; Bhutani, K.K. Fate of embelin in pippalyadi yoga, an ayurvedic oral contraceptive: Structure of embelin-borax complex and evaluation of anti-fertility activity. Indian J. Chem., 2007, 46B, 320-325.
Gao, Y.; Li, J.; Xu, X.; Wang, S.; Yang, Y.; Zhou, J.; Zhang, L.; Zheng, F.; Li, X.; Wang, B. Embelin attenuates adipogenesis and lipogenesis through activating canonical Wnt signaling and inhibits high-fat diet-induced obesity. Int. J. Obes., 2017, 41(5), 729-738.
[] [PMID: 28163317]
Chaudhari, H.S.; Bhandari, U.; Khanna, G. Preventive effect of embelin from embelia ribes on lipid metabolism and oxidative stress in high-fat diet-induced obesity in rats. Planta Med., 2012, 78(7), 651-657.
[] [PMID: 22450777]
Bhandari, U. Effect of embelin in monosodium glutamate induced obesity in male neonatal Wistar rats. Atheroscler. Suppl., 2018, 32, 138.
Kumara Swamy, H.M.; Krishna, V.; Shankarmurthy, K.; Abdul Rahiman, B.; Mankani, K.L.; Mahadevan, K.M.; Harish, B.G.; Raja Naika, H. Wound healing activity of embelin isolated from the ethanol extract of leaves of Embelia ribes Burm. J. Ethnopharmacol., 2007, 109(3), 529-534.
[] [PMID: 17034970]
Mizuno, C.S.; Rimando, A.M.; Duke, S.O. Phytotoxic activity of quinones and resorcinolic lipid derivatives. J. Agric. Food Chem., 2010, 58(7), 4353-4355.
[] [PMID: 20232851]
Campbell, G.R.; Spector, S.A. DIABLO/SMAC mimetics selectively kill HIV-1-infected resting memory CD4+ T cells: a potential role in a cure strategy for HIV-1 infection. Autophagy, 2019, 15(4), 744-746.
[] [PMID: 30653393]

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Year: 2020
Published on: 24 April, 2020
Page: [396 - 407]
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DOI: 10.2174/1389557519666191015202723
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