Biocatalytic Synthesis of Flavonoid Esters by Lipases and Their Biological Benefits

Abstract

Several studies have described important biological activities of flavonoids such as coronary heart disease prevention, hepatoprotective, anti-inflammatory and anticancer activities, enzyme inhibition activity, and antibacterial, antifungal, and antiviral activities. Flavonoids show promising activity as natural plant-based antioxidants due to their antioxidant and free radical scavenging properties. However, their primary applications as antioxidants in the pharmaceutical, cosmetic, and food industries are limited because of their moderately hydrophilic nature. Enzymatic acylation of natural polyphenols with fatty acids or other acyl donors has been suggested for improving the lipophilic nature of the glycosylated flavonoids. This approach increases flavonoid solubility and stability in lipophilic systems. Acylation of flavonoids with different acyl donors may also introduce beneficial properties to the molecule, such as penetration through the cell membrane and improved antioxidant, antimicrobial, anti-inflammatory, antiproliferative, cytogenetic, and enzyme inhibition activities. Chemical methods for the synthesis of flavonoid esters lead to the formation of side products and the simultaneous decomposition of the flavonoids due to harsh reaction conditions. In contrast, biocatalytic acylation of flavonoids by lipases offers advantages associated to the wide availability of these enzymes, their low cost, chemo-, regio-, and enantioselectivity, mild condition processing and non-requirement of cofactors. This article is focused on the recent development of lipase-catalyzed synthesis of flavonoid esters and the impact of the acylation reaction on their biological activities.

Key words

flavonoids - lipase - acylation - biocatalysis

• References

• 1 Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal 2013; 2013: 162750
• 2 Danihelová M, Veverka M, Šturdík E, Jantová S. Antioxidant action and cytotoxicity on HeLa and NIH-3T3 cells of new quercetin derivatives. Interdiscip Toxicol 2013; 6: 209-216
• 3 Zhao W, Sun J, Xiang H, Zeng YY, Li XB, Xiao H, Chen DY, Ma RL. Synthesis and biological evaluation of new flavonoid fatty acid esters with anti-adipogenic and enhancing glucose consumption activities. Bioorg Med Chem 2011; 19: 3192-3203
• 4 Fukami H, Nakao M, Namikawa K, Maeda M. Esterified catechin, process for producing the same, food and drink or cosmetic containing the same. EP Patent 1849779, 2007
• 5 Gao C, Mayon P, Macmanus DA, Vulfson EN. Novel enzymatic approach to the synthesis of flavonoid glycosides and their esters. Biotechnol Bioeng 2000; 71: 235-243
• 6 Katsoura MH, Polydera AC, Tsironis L, Tselepis AD, Stamatis H. Use of ionic liquids as media for the biocatalytic preparation of flavonoid derivatives with antioxidant potency. J Biotechnol 2006; 123: 491-503
• 7 Mellou F, Loutrari H, Stamatis H, Roussos C, Kolisis FN. Enzymatic esterification of flavonoids with unsaturated fatty acids: effect of the novel esters on vascular endothelial growth factor release from K562 cells. Process Biochem 2006; 41: 2029-2034
• 8 Mellou F, Lazari D, Skaltsa H, Tselepis A, Kolisis F, Stamatis H. Biocatalytic preparation of acylated derivatives of flavonoid glycosides enhances their antioxidant and antimicrobial activity. J Biotechnol 2005; 116: 295-304
• 9 Ardhaoui M, Falcimaigne A, Ognier S, Engasser JM, Moussou P, Pauly G, Ghoul M. Effect of acyl donor chain length and substitutions pattern on the enzymatic acylation of flavonoids. J Biotechnol 2004; 110: 265-271
• 10 Ardhaoui M, Falcimaigne A, Engasser JM, Moussou P, Pauly G, Ghoul M. Acylation of flavonoids using lipase of Candida antarctica as biocatalyst. J Mol Catal B Enzym 2004; 29: 63-67
• 11 Ardhaoui M, Falcimaigne A, Engasser JM, Moussou P, Ghoul M. Enzymatic synthesis of new aromatic and aliphatic esters of flavonoids using Candida antarctica lipase as biocatalyst. Biocatal Biotransformation 2004; 22: 253-259
• 12 Enaud E, Humeau C, Piffaut B, Girardin M. Enzymatic synthesis of new aromatic esters of phloridzin. J Mol Catal B Enzym 2004; 27: 1-6
• 13 Gayot S, Santarelli X, Coulon D. Modification of flavonoid using lipase in nonconventional media: effect of the water content. J Biotechnol 2003; 101: 29-36
• 14 Kontogianni A, Skouridou V, Serteti V, Stamatis H, Kolisis FN. Lipase-catalyzed esterification of rutin and naringin with fatty acids of medium carbon chain. J Mol Catal B Enzym 2003; 21: 59-62
• 15 Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis 2006; 9: 68-76
• 16 Clark J. Green chemistry: challenges and opportunities. Green Chem 1999; 1: 1-8
• 17 Schmid A, Dordick J, Hauer B, Kiener A, Wubbolts M, Witholt B. Industrial biocatalysis today and tomorrow. Nature 2001; 409: 258-268
• 18 Chebil L, Humeau C, Falcimaigne A, Engasser JM, Ghoul M. Enzymatic acylation of flavonoids. Process Biochem 2006; 41: 2237-2251
• 19 Viskupicova J, Ondrejovic M, Sturdik E. The potential and practical applications of acylated flavonoids. Pharmazie 2009; 64: 355-360
• 20 Xanthakis E, Theodosiou E, Magkouta S, Stamatis H, Loutrari H, Roussos C, Kolisis F. Enzymatic transformation of flavonoids and terpenoids: structural and functional diversity of the novel derivatives. Pure Appl Chem 2010; 82: 1-16
• 21 Tarahovsky YS, Kim YA, Yagolnik EA, Muzafarov EN. Flavonoid-membrane interactions: involvement of flavonoid-metal complexes in raft signaling. Biochim Biophys Acta 2014; 1838: 1235-1246
• 22 Van Dijk C, Driessen AJ, Recourt K. The uncoupling efficiency and affinity of flavonoids for vesicles. Biochem Pharmacol 2000; 60: 1593-1600
• 23 Kyriakou E, Primikyri A, Charisiadis P, Katsoura M, Gerothanassis IP, Stamatis H, Tzakos AG. Unexpected enzyme-catalyzed regioselective acylation of flavonoid aglycones and rapid product screening. Org Biomol Chem 2012; 10: 1739-1742
• 24 Collins AM, Kennedy MJ. Biotransformations and bioconversions in New Zealand: past endeavours and future potential. Australas Biotechnol 1999; 9: 86-94
• 25 Nagasawa T, Yamada H. Microbial production of commodity chemicals. Pure Appl Chem 1995; 67: 1241-1256
• 26 Rajendram A, Palanisamy A, Thangavelu V. Lipase catalyzed ester synthesis for food processing industries. Braz Arch Biol Technol 2009; 52: 207-219
• 27 Ferreira-Dias S, Sandoval G, Plou F, Valero F. The potential use of lipases in the production of fatty acid derivatives for the food and nutraceutical industries. Electron J Biotechn 2013; 16: 1
• 28 Degn P, Pedersen LH, Duus J, Zimmerman W. Lipase-catalysed synthesis of glucose fatty acid esters in tert-butanol. Biotechnol Lett 1999; 21: 275-280
• 29 Anderson EM, Larsson KM, Kirk O. One biocatalyst – many applications: the use of Candida Antarctica B lipase in organic synthesis. Biocatal Biotransformation 1998; 6: 181-204
• 30 Cordova A, Iversen T, Hult K, Martinelle M. Lipase-catalysed formation of macrocycles by ring-opening polymerisation of ε-caprolactone. Polymer (Guildf) 1998; 39: 6519-6524
• 31 Lutz S. Engineering lipase B from Candida antarctica . Tetrahedron Asymmetry 2004; 15: 2743-2748
• 32 Araújo ME, Contesini FJ, Franco YEM, Sawaya ACF, Alberto TG, Dalfré N, Carvalho PO. Optimized enzymatic synthesis of hesperidin fatty acid esters in a two-phase system containing ionic liquid. Molecules 2011; 16: 7171-7182
• 33 De Oliveira EB, Humeau C, Chebil L, Maia ER, Dehez F, Maigret B, Ghoul M, Engasser JM. A molecular modelling study to rationalize the regioselectivity in acylation of flavonoid glycosides catalyzed by Candida antarctica lipase B. J Mol Catal B Enzym 2009; 59: 96-105
• 34 Razak NNA, Annuar MSM. Enzymatic synthesis of flavonoid ester: Elucidation of its kinetic mechanism and equilibrium thermodynamic behavior. Ind Eng Chem Res 2015; 54: 5604-5612
• 35 Trodler P, Pleiss J. Modeling structure and flexibility of Candida antarctica lipase B in organic solvents. BMC Struct Biol 2008; 8: 9
• 36 Nakajima N, Ishihara K, Itoh T, Furuya T, Hamada H. Lipase catalysed direct and regioselective acylation of flavonoid glucoside for mechanistic investigation of stable plant pigments. J Biosci Bioeng 1999; 61: 1926-1928
• 37 Danieli B, Luisetti M, Sampognaro G, Carrea G, Riva S. Regioselective acylation of polyhydroxylated natural compounds catalyzed by Candida antarctica lipase B (Novozym 435) in organic solvents. J Mol Catal B Enzym 1997; 3: 193-201
• 38 Salem JH, Humeau C, Chevalot I, Harscoat-Schiavo C, Vanderesse R, Blanchard F, Fick M. Effect of acyl donor chain length on isoquercitrin acylation and biological activities of corresponding esters. Process Biochem 2010; 45: 382-389
• 39 Viskupicova J, Danihelova M, Ondrejovic M, Liptaj T, Sturdik E. Lipophilic rutin derivatives for antioxidant protection of oil-based foods. Food Chem 2010; 123: 45-50
• 40 Passicos E, Santarelli X, Coulon D. Regioselective acylation of flavonoids catalyzed by immobilized Candida antarctica lipase under reduced pressure. Biotechnol Lett 2004; 26: 1073-1076
• 41 Theodosiou E, Loutrari H, Stamatis H, Roussos C, Kolisis FN. Biocatalytic synthesis and antitumor activities of novel silybin acylated derivatives with dicarboxylic acids. N Biotechnol 2011; 28: 342-348
• 42 Salem JH, Chevalot I, Harscoat-Schiavo C, Paris C, Fick M, Humeau C. Biological activities of flavonoids from Nitraria retusa (Forssk.) Ach. and their acylated derivatives. Food Chem 2011; 124: 486-494
• 43 Katsoura MH, Polydera AC, Katapodis P, Kolisis FN, Stamatis H. Effect of different reaction parameters on the lipase-catalyzed selective acylation of polyhydroxylated natural compounds in ionic liquids. Process Biochem 2007; 42: 1326-1334
• 44 Céliz G, Daz M. Biocatalytic preparation of alkyl esters of citrus flavanone glucoside prunin in organic media. Process Biochem 2011; 46: 94-100
• 45 Lue BM, Guo Z, Glasius M, Xu X. Scalable preparation of high purity rutin fatty acids esters. J Am Oil Chem Soc 2010; 87: 551-561
• 46 Almeida VM, Branco CRC, Assis SA, Vieira IJC, Braz-Filho R, Branco A. Synthesis of naringin 6″-ricinoleate using immobilized lipase. Chem Cent J 2012; 6: 41-47
• 47 Céliz G, Martearena MR, Scaroni E, Daz M. Kinetic study of the alkyl flavonoid ester prunin-6″-O-laurate synthesis in acetone catalysed by immobilised Candida antarctica lipase B. Biochem Eng J 2012; 69: 69-74
• 48 Ziaullah KS, Bhullar SN, Warnakulasuriya HP, Rupasinghe V. Biocatalytic synthesis, structural elucidation, antioxidant capacity and tyrosinase inhibition activity of long chain fatty acid acylated derivatives of phloridzin and isoquercitrin. Bioorg Med Chem 2013; 21: 684-692
• 49 Viskupicova J, Ondrejovic M, Maliar T. Enzyme-mediated preparation of flavonoid esters and their applications. Biochemistry 2012; 10: 263-278
• 50 Danihelova M, Viskupicova J, Sturdik E. Lipophilization of flavonoids for their food, therapeutic and cosmetic applications. Acta Chim Slov 2012; 5: 59-69
• 51 Welton T. Room-temperature ionic liquids. Solvents for synthesis and catalysis. Chem Rev 1999; 99: 2071-2083
• 52 Park S, Kazlauskas RJ. Biocatalysis in ionic liquids – advantages beyond green technology. Curr Opin Biotechnol 2003; 14: 432-437
• 53 Moon YH, Lee SM, Ha SH, Koo YM. Enzyme-catalyzed reactions in ionic liquids. Korean J Chem Eng 2006; 23: 247-263
• 54 Van Rantwijk F, Sheldon RA. Biocatalysis in ionic liquids. Chem Rev 2007; 107: 2757-2785
• 55 Park S, Kazlauskas RJ. Improved preparation and use of room temperature ionic liquids in lipase-catalyzed enantio- and regioselective acylations. J Org Chem 2001; 66: 8395-8401
• 56 De Diego T, Lozano P, Gmouh S, Vaultier M, Iborra JL. Understanding structure-stability relationships of Candida antarctica lipase B in ionic liquids. Biomacromolecules 2005; 6: 1457-1464
• 57 Lue BM, Nielsen NS, Jacobsen C, Hellgren L, Guo Z, Xu X. Antioxidant properties of modified rutin esters by DPPH, reducing power, iron chelation and human low density lipoprotein assays. Food Chem 2010; 123: 221-230
• 58 Arroyo M, Sánchez-Montero JM, Sinisterra JV. Thermal stabilization of immobilized lipase B from Candida antarctica on different supports: effect of water activity on enzymatic activity in organic media. Enzyme Microb Technol 1999; 24: 3-12
• 59 Zaks A, Klibanov AM. Enzymatic catalysis in nonaqueous solvents. J Biol Chem 1988; 263: 3194-3201
• 60 Stevenson DE, Wibisono R, Jensen DJ, Stanley RA, Cooney JM. Direct acylation of flavonoid glycosides with phenolic acids catalysed by Candida antarctica lipase B (Novozym 435). Enzyme Microb Technol 2006; 39: 1236-1241
• 61 Pirozzi D, Greco jr. FG. Activity and stability of lipases in the synthesis of butyl lactate. Enzyme Microb Technol 2004; 34: 94-100
• 62 Zhao H. Effect of ions and other compatible solutes on enzyme activity, and its implication for biocatalysis using ionic liquids. J Mol Catal B Enzym 2005; 37: 16-25
• 63 Jewur SS. Química de zeólitas e catálise. Quim Nova 1985; 8: 99-105
• 64 Ballesteros A, Plou FJ, Alcade M, Ferrer M, Garcia-Arellano H, Reyes-Duarte D, Ghazi I. Enzymatic Synthesis of Sugar Esters and Oligosaccharides from renewable Resources. In: Patel RN. ed. Biocatalysis in the pharmaceutical and Biotechnology Industries. Boca Raton: CRC Press; 2006: 463-488
• 65 Pleiss J, Fischer M, Schmid RD. Anatomy of lipase binding sites: the scissile fatty acid binding site. Chem Phys Lipids 1998; 93: 67-80
• 66 Viskupicova J, Ondrejovič M. Effect of fatty acid Chain Length on enzymatic Esterification of Rutin. In: Martin Pipíška. ed. Book of Abstracts of the 1st International Conference of Applied Natural Sciences. Trnava, Slovakia: UCM; 2007: 59
• 67 Patti A, Piattelli M, Nicolosi G. Use of Mucor miehei lipase in the preparation of long chain 3-O-acylcatechins. J Mol Catal B Enzym 2000; 10: 577-582
• 68 Solomons TWG, Fryhle CB. Organic Chemistry, 7th ed. New York: Wiley; 2001
• 69 Kontogianni A, Skouridou V, Sereti V, Stamatis H, Kolisis FN. Regioselective acylation of flavonoids catalyzed by lipase in low toxicity media. Eur J Lipid Sci Tech 2001; 103: 655-660
• 70 Ishihara K, Nakajima N. Structural aspects of acylated plant pigments: stabilization of flavonoid glucosides and interpretation of their functions. J Mol Catal B Enzym 2003; 23: 411-417
• 71 Ghoul M, Engasser JM, Moussou P, Pauly G, Ardhaoui M, Falcimaigne A. Enzymatic production of acyl flavonoid derivatives. US Patent 20060115880 A1, 2006
• 72 Viskupicova J, Maliar T, Psenakova I, Sturdik E. Enzymatic acylation of naringin. Nova Biotechnol 2006; 6: 149-159
• 73 Kappe CO, Dallinger D. Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature. Mol Divers 2009; 13: 71
• 74 Batistella L, Lerin LA, Brugnerotto P, Danielli AJ, Trentin CM, Popiolski A, Treichel H, Oliveira JV, De Oliveira D. Ultrasound-assisted lipase-catalyzed transesterification of soybean oil in organic solvent system. Ultrason Sonochem 2012; 19: 452-458
• 75 Ziaullah. Rupasinghe HP. An efficient microwave-assisted enzyme-catalyzed regioselective synthesis of long chain acylated derivatives of flavonoid glycosides. Tetrahedron Lett 2013; 54: 1933-1937
• 76 La Cara F, dʼAuria S, Scarfi MR, Zeni O, Massa R, dʼAmbrioso G, Franceschetti G, De Rosa M, Rossi M. Microwave exposure effect on a thermophilic alcohol desidrogenase. Protein Pept Lett 1999; 6: 155-162
• 77 Mazumder S, Laskar DD, Prajapati D, Roy MK. Microwave-induced enzyme-catalyzed chemoselective reduction of organic azides. Chem Biodivers 2004; 1: 925-929
• 78 Hobuss CB, Venzke D, Pacheco BS, Souza AO, Santos MAZ, Moura S, Quina FH, Fiametti KG, Oliveira JV, Pereira CMP. Ultrasound-assisted synthesis of aliphatic acid esters at room temperature. Ultrason Sonochem 2012; 19: 387-389
• 79 Zengh MM, Wang L, Huang FH, Dong L, Guo PM, Deng QC, Li WL, Zheng C. Ultrasonic pretreatment for lipase-catalyed synthesis of phytosterol esters with different acyl donors. Ultrason Sonochem 2012; 19: 1015-1020
• 80 Ziaullah. Rupasinghe HP. Sonochemical enzyme-catalyzed regioselective acylation of flavonoid glycosides. Bioorg Chem 2016; 65: 17-25
• 81 Medina I, Alcantara D, Gonzalez MJ, Torres P, Lucas R, Roque J, Plou FJ, Morales JC. Antioxidant activity of resveratrol in several fish lipid matrices: effect of acylation and glucosylation. J Agric Food Chem 2010; 58: 9778-9786
• 82 Shahidi F. Nutraceutical, functional foods and dietary supplements in health and disease. J Food Drug Anal 2012; 20: 226-230
• 83 Warnakulasuriya SN, Ziaullah. Rupasinghe HPV. Long chain fatty acid acylated derivatives of quercetin-3-O-glucoside as antioxidants to prevent lipid oxidation. Biomolecules 2014; 4: 980-993
• 84 Ma X, Yan R, Yu S, Lu Y, Li Z, Lu H. Enzymatic acylation of isoorientin and isovitexin from bamboo-leaf extracts with fatty acids and antiradical activity of the acylated derivatives. J Agric Food Chem 2012; 60: 10844-10849
• 85 Xu J, Qian J, Li S. Enzymatic acylation of isoorientin isolated from antioxidant of bamboo leaves with palmitic acid and antiradical activity of the acylated derivatives. Eur Food Res Technol 2014; 239: 661-667
• 86 Milisavljević A, Stojanović M, Carević M, Mihailović M, Veličković D, Milosavić N, Bezbradica D. Lipase-catalyzed esterification of phloridzin: Acyl donor effect on enzymatic affinity and antioxidant properties of esters. Ind Eng Chem Res 2014; 53: 16644-16651
• 87 Zhu S, Li Y, Li Z, Ma C, Lou Z, Yokoyama W, Wang H. Lipase-catalyzed synthesis of acetylated EGCG and antioxidant properties of the derivatives. Food Res Int 2014; 56: 279-286
• 88 Karabin M, Hudcova T, Jelinek L, Dostalek P. Biotransformations and biological activities of hop flavonoids. Biotechnol Adv 2015; 33: 1063-1090
• 89 Ravishankar D, Rajora AK, Greco F, Osborn HMI. Flavonoids as prospective compounds for anti-cancer therapy. Int J Biochem Cell Biol 2013; 45: 2821-2831
• 90 Liu HL, Jiang WB, Xie MX. Flavonoids: recent advances as anticancer drugs. Recent Pat Anticancer Drug Discov 2010; 5: 152-164
• 91 Nair SVG, Ziaullah. Rupasinghe HPV. Fatty acid esters of phloridzin induce apoptosis of human liver cancer cells through altered gene expression. PLoS One 2014; 9: e107149
• 92 Sudan S, Rupasinghe HPV. Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in hepatocellular carcinoma HepG2 cells. Exp Biol Med 2015; 240: 1452-1464
• 93 Warnakulasuriya SN, Ziaullah. Rupasinghe HPV. Novel long chain fatty acid derivatives of quercetin-3-O-glucoside reduce cytotoxicity induced by cigarette smoke toxicants in human fetal lung fibroblasts. Eur J Pharmacol 2016; 781: 128-138
• 94 Warnakulasuryia SN, Ziaullah. Rupasinghe HP. Long chain fatty acid esters of quercetin-O-glucoside attenuate H₂O₂-induced acute cytotoxicity in human lung fibroblasts and primary hepatocytes. Molecules 2016; 21: 452
• 95 Rathee P, Chaudhary H, Rathee S, Rathee D, Kumar V, Kohli K. Mechanism of action of flavonoids as anti-inflammatory agents: a review. Inflamm Allergy Drug Targets 2009; 8: 229-235
• 96 Hoang TK, Huynh TK, Nguyen T. Synthesis, characterization, anti-inflammatory and anti-proliferative activity against MCF-7 cells of O-alkyl and O-acyl flavonoid derivatives. Bioorg Chem 2015; 63: 45-52
• 97 Liu LY, Jin C, Zhang Y. Lipophilic phenolic compounds (Lipo-PCS): emerging antioxidants applied in lipid systems. RSC Adv 2014; 6: 2879-2891
• 98 Tubaro A, Del Negro P, Bianchi P, Romussi G, Della Loggia R. Topical anti-inflammatory activity of a new acylated flavonoid. Agents Actions 1989; 26: 1-2
• 99 Shen Y, Zhang J, Sheng R, Dong X, He Q, Yang B, Hu Y. Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors. J Enzyme Inhib Med Chem 2009; 24: 372-380
• 100 Li RS, Wang XB, Xu XJ, Kong LY. Design, synthesis and evaluation of flavonoid derivatives as potential multifunctional acetylcholinesterase inhibitors against Alzheimerʼs disease. Bioorg Med Chem Lett 2013; 23: 2636-2641
• 101 Harborne JB, Williams CA. Advances in flavonoid research since 1992. Phytochemistry 2000; 55: 481-504
• 102 Mossou P, Falcimaigne A, Ghoul M, Danoux L, Pauly G. Esters of flavonoids with w-substituted C6 – C22 fatty acids. US Patent 20070184098, 2007
• 103 Lee SJ, Baek HJ, Lee CH, Kim HP. Antiinflammatory activity of isoflavonoids from Pueraria radix and biochanin A derivatives. Arch Pharm Res 1994; 17: 31-35
• 104 Park KD, Park YS, Cho SJ, Sun WS, Kim SH, Jung DH. Antimicrobial activity of 3-O-acyl-(−)-epicatechin and 3-O-acyl-(+)- catechin derivatives. Planta Med 2004; 70: 272-276
• 105 Amen HY, Marzouka AM, Zaghloula MG, Afifia MS. A new acylated flavonoid tetraglycoside with anti-inflammatory activity from Tipuana tipu leaves. Nat Prod Res 2015; 29: 511-517
• 106 Albert A, Courbat P, Weith A. Process for the preparation of O-substituted derivatives of (+)-cyanidan-3-01. US Patent 4255336, 1981
• 107 Sekhon-Loodu S, Ziaullah Z, Rupasinghe HPV, Wang Y, Kulka M, Shahidi F. Novel quercetin-3-O-glucoside eicosapentaenoic acid ester ameliorates inflammation and hyperlipidemia. Inflammopharmacology 2015; 23: 173-185
• 108 Sekhon-Loodu S, Ziaullah. Rupasinghe HP. Docosahexaenoic acid ester of phloridzin inhibits lipopolysaccharide-induced inflammation in THP-1 differentiated macrophages. Int Immunopharmacol 2015; 1: 199-206
• 109 Rauha JP, Remes S, Heinonen M, Hopia A, Kähkönen M, Kujala T, Pihlaja K, Vuorela H, Vuorela P. Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds. Int J Food Microbiol 2000; 56: 3-12
• 110 Aziz NH, Farag SE, Mousa LA, Abo-Zaid MA. Comparative antibacterial and antifungal effects of some phenolic compounds. Microbios 1998; 93: 43-54
• 111 Stapleton PD, Shah S, Hamilton-Miller JMT, Hara Y, Nagaoka Y, Kumagai A, Uesato S, Taylor PW. Anti-Staphylococcus aureus activity and oxacillin resistance modulating capacity of 3-O-acyl-catechins. Int J Antimicrob Agents 2004; 24: 374-380
• 112 Kodelia G, Athanasiou K, Kolisis FN. Enzymatic synthesis of butyryl-rutin ester in organic solvents and its cytogenetic effects in mammalian cells in culture. Appl Biochem Biotechnol 1994; 44: 205-212
• 113 Park KD, Cho SJ. Synthesis and antimicrobial activities of 3-O-alkyl analogues of (þ)-catechin: improvement of stability and proposed action mechanism. Eur J Med Chem 2010; 45: 1028-1033
• 114 Grippa E, Valla R, Battinelli L, Mazzanti G, Saso L, Silvestrini B. Inhibition of Candida rugosa lipase by berberine and structurally related alkaloids, evaluated by high-performance liquid chromatography. Biosci Biotechnol Biochem 1999; 63: 1557-1562
• 115 Gatto MT, Falcocchio S, Grippa E, Mazzanti G, Battinelli L, Nicolosi G, Lambustab D, Saso L. Antimicrobial and anti-lipase activity of quercetin and its C2–C16 3-O-acyl-esters. Bioorg Med Chem 2002; 10: 269-272
• 116 Salas MP, Céliz G, Geronazzo H, Daz M, Resnik SL. Antifungal activity of natural and enzymatically-modified flavonoids isolated from citrus species. Food Chem 2011; 124: 1411-1415
• 117 Muzna S, Divya D, Kamat SD, Kamat D. Antifungal activity of lipase modified flavonoids from citrus limetta. Int J Pharm Pharm Sci 2014; 6: 116-118
• 118 Harmalkar A, Shaikh M, Kamat S, Kamat D. Enzyme assisted transformation of glycosides. South As J Biol Sci 2013; 3: 40-45
• 119 Hanasaki Y, Ogawa S, Fukui S. The correlation between active oxygen scavenging and antioxidative effects of flavonoids. Free Radic Biol Med 1994; 16: 845-850
• 120 Cos P, Ying L, Calomme M, Hu JP, Cimanga K, Van Poel B. Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers. J Nat Prod 1998; 61: 71-76
• 121 Lin CM, Chen CS, Chen CT, Liang YC, Lin JK. Molecular modeling of flavonoids that inhibits xanthine oxidase. Biochem Biophys Res Commun 2002; 294: 167-172
• 122 Rao RJ, Tiwari A, Kumar US, Reddy SV, Ali S, Rao JM. Novel 3-O-acyl mesquitol analogues as free-radical scavengers and enzyme inhibitors: synthesis, biological evaluation and structure-activity relationship. Bioorg Med Chem Lett 2003; 13: 2777-2780
• 123 Lio M, Moriyama A, Matsumoto Y, Takaki N, Fukumoto M. Inhibition of xanthine oxidase by flavonoids. Agric Biol Chem 1985; 49: 2173-2176
• 124 Fear G, Komarnytsky S, Raskin I. Protease inhibitors and their peptidomimetic derivatives as potential drugs. Pharmacol Ther 2007; 113: 354-368
• 125 Clark JM, Jenkins TE, Katz BA, Stroud RM. Metal complexed serine protease inhibitors. US Patent 5693515A, 1997
• 126 Viskupicova J, Danihelova M, Majekova M, Liptaj T, Sturdik E. Polyphenol fatty acid esters as serine protease inhibitors: a quantum-chemical QSAR analysis. J Enzyme Inhib Med Chem 2012; 27: 800-809
• 127 Lin SF, Lin YH, Lin M, Kao YF, Wang RW, Teng LW, Chuang SH, Chang JM, Yuan TT, Fu KC, Huang KP, Lee YS, Chiang CC, Yang SC, Lai CL, Liao CB, Chen P, Lin YS, Lai KT, Huang HJ, Yang JY, Liu CW, Wei WY, Chen CK, Hiipakka RA, Liao S, Huang JJ. Synthesis and structure-activity relationship of 3-O-acylated (e)-epigallocatechins as 5α-reductase inhibitors. Eur J Med Chem 2010; 45: 6068-6076
• 128 Kim YJ, Uyama H. Tyrosinase inhibitors from natural and synthetic sources: structure, inhibition mechanism and perspective for the future. Cell Mol Life Sci 2005; 62: 1707-1723
• 129 Khan MT. Novel tyrosinase inhibitors from natural resources – their computational studies. Curr Med Chem 2012; 19: 2262-2272
• 130 Sheng R, Lin X, Zhang J, Chol KS, Huang W, Yang B, He Q, Hu Y. Design, synthesis and evaluation of flavonoid derivatives as potent AChE inhibitors. Bioorg Med Chem 2009; 17: 6692-6698
• 131 Augustyniak A, Bartosz G, Cipak A, Duburs G, Horakova L, Luczaj W, Majekova M, Odysseos AD, Rackova L, Skrzydlewska E, Stefek M, Strosova M, Tirzitis G, Viskupicova J, Vraka PS, Zarkovic N. Natural and synthetic antioxidants: an updated overview. Free Radic Res 2010; 44: 1216-1262
• 132 Viskupicova J, Majekova M, Horakova L. Inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA1) by rutin derivatives. J Muscle Res Cell Motil 2015; 36: 183-194
• 133 Bhullar KS, Ziaullah. Rupasinghe HPV. In vitro regulation of enzymes of the renin-angiotensin-aldosterone system by isoquercitrin, phloridzin and their long chain fatty acid derivatives. Funct Food Health Dis 2014; 4: 208-221