A series of isoquercitrin (quercetin-3-O-β-d-glucopyranoside) esters with mono- or dicarboxylic acids was designed to modulate hydro- and lipophilicity and biological properties. Esterification of isoquercitrin was accomplished by direct chemoenzymatic reaction using Novozym 435 (lipase from Candida antarctica), which accepted C₅- to C12-dicarboxylic acids; the shorter ones, such as oxalic (C₂), malonic (C₃), succinic (C₄) and maleic (C₄) acids were not substrates of the lipase. Lipophilicity of monocarboxylic acid derivatives, measured as log P, increased with the chain length. Esters with glutaric and adipic acids exhibited hydrophilicity, and the dodecanedioic acid hemiester was more lipophilic. All derivatives were less able to reduce Folin-Ciocalteau reagent (FCR) and scavenge DPPH (1,1-diphenyl-2-picrylhydrazyl) than isoquercitrin; ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) radical-scavenging activity was comparable. Dodecanoate and palmitate were the least active in FCR and ABTS scavenging; dodecanoate and hemiglutarate were the strongest DPPH scavengers. In contrast, most derivatives were much better inhibitors of microsomal lipoperoxidation than isoquercitrin; butyrate and hexanoate were the most efficient. Anti-lipoperoxidant activity of monocarboxylic derivatives, except acetates, decreased with increasing aliphatic chain. The opposite trend was noted for dicarboxylic acid hemiesters, isoquercitrin hemidodecanedioate being the most active. Overall, IQ butyrate, hexanoate and hemidodecanedioate are the most promising candidates for further studies.

Institute of Chemistry University of Rostock Albert Einstein Str 3a GE 18059 Rostock Germany

Laboratory of Biotransformation Institute of Microbiology Czech Academy of Sciences 5 and 237;deňsk and 225; 1083 CZ 142 20 Prague Czech Republic

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Shahidi F., Janitha P.K., Wanasundara P.D. Phenolic antioxidants. Crit. Rev. Food Sci. 1992;32:67–103. doi: 10.1080/10408399209527581. PubMed DOI

Heim K.E., Tagliaferro A.R., Bobilya D.J. Flavonoid antioxidants: Chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 2002;13:572–584. doi: 10.1016/S0955-2863(02)00208-5. PubMed DOI

Quideau S., Deffieux D., Douat-Casassus C., Pouysegu L. Plant polyphenols: Chemical properties, biological activities and synthesis. Angew. Chem. Int. Ed. 2011;50:586–621. doi: 10.1002/anie.201000044. PubMed DOI

Hollman P.C.H., van Trijp J.M.P., Buysman M.N.C.P., Van der Gaag M.S., Mengelers M.J.B., de Vries J.H.M., Katan M.B. Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS Lett. 1997;418:152–156. doi: 10.1016/S0014-5793(97)01367-7. PubMed DOI

D’Andrea G. Quercetin: A flavonol with multifaceted therapeutic applications? Fitoterapia. 2015;106:256–271. doi: 10.1016/j.fitote.2015.09.018. PubMed DOI

Boots A.W., Haenen G.R.M.M., Bast A. Health effects of quercetin: From antioxidant to nutraceutical. Eur. J. Pharmacol. 2008;585:325–337. doi: 10.1016/j.ejphar.2008.03.008. PubMed DOI

Okamoto T. Safety of quercetin for clinical application (Review) Int. J. Mol. Med. 2005;16:275–278. doi: 10.3892/ijmm.16.2.275. PubMed DOI

Dajas F. Life or death: Neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol. 2012;143:383–396. doi: 10.1016/j.jep.2012.07.005. PubMed DOI

Harwood M., Danielewska-Nikiel B., Borzelleca J.F., Flamm G.W., Williams G.M., Lines T.C. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcino genic properties. Food Chem. Toxicol. 2007;45:2179–2205. doi: 10.1016/j.fct.2007.05.015. PubMed DOI

Sharma S., Ali A., Ali J., Sahni J.K., Baboota S. Rutin: Therapeutic potential and recent advances in drug delivery. Expert Opin. Investig. Drug. 2013;22:1063–1079. doi: 10.1517/13543784.2013.805744. PubMed DOI

Valentová K., Vrba J., Bancířová M., Ulrichová J., Křen V. Isoquercitrin: Pharmacology, toxicology, and metabolism. Food Chem. Toxicol. 2014;68:267–282. doi: 10.1016/j.fct.2014.03.018. PubMed DOI

Gerstorferová D., Fliedrová B., Halada P., Marhol P., Křen V., Weignerová L. Recombinant α-l-rhamnosidase from Aspergillus terreus in selective trimming of rutin. Process Biochem. 2012;47:828–835. doi: 10.1016/j.procbio.2012.02.014. DOI

Chebil L., Humeau C., Anthoni J., Dehez F., Engasser J.M., Ghoul M. Solubility of flavonoids in organic solvents. J. Chem. Eng. Data. 2007;52:1552–1556. doi: 10.1021/je7001094. DOI

Chebil L., Bouroukba M., Gaiani C., Charbonel C., Khaldi M., Engasser J.M., Ghoul M. Elucidation of the kinetic behavior of quercetin, isoquercitrin, and rutin solubility by physicochemical and thermodynamic investigation. Ind. Eng. Chem. Res. 2013;52:1464–1470. doi: 10.1021/ie3029202. DOI

Makino T., Shimizu R., Kanemaru M., Suzuki Y., Moriwaki M., Mizukami H. Enzymatically modified isoquercitrin, α-oligoglucosyl quercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. Biol. Pharm. Bull. 2009;32:2034–2040. doi: 10.1248/bpb.32.2034. PubMed DOI

Biedermann D., Vavříková E., Cvak L., Křen V. Chemistry of silybin. Nat. Prod. Rep. 2014;31:1138–1157. doi: 10.1039/C3NP70122K. PubMed DOI

Danieli B., Bertario A. Chemoenzymatic synthesis of 6’’-O-(3-arylprop-2-enoyl) derivatives of the flavonol glucoside isoquercitrin. Helv. Chim. Acta. 1993;76:2981–2991. doi: 10.1002/hlca.19930760823. DOI

Chebil L., Humeau C., Falcimaigne A., Engasser J.M., Ghoul M. Enzymatic acylation of flavonoids. Process Biochem. 2006;41:2237–2251. doi: 10.1016/j.procbio.2006.05.027. DOI

Ardhaoui M., Falcimaigne A., Engasser J.M., Moussou P., Pauly G., Ghoul M. Acylation of natural flavonoids using lipase of Candida antarctica as biocatalyst. J. Mol. Catal. B-Enzym. 2004;29:63–67. doi: 10.1016/j.molcatb.2004.02.013. DOI

Chebil L., Anthoni J., Humeau C., Gerardin C., Engasser J.M., Ghoul M. Enzymatic acylation of flavonoids: Effect of the nature of the substrate, origin of lipase and operating conditions on conversion yield and regioselectivity. J. Agric. Food Chem. 2007;55:9496–9502. doi: 10.1021/jf071943j. PubMed DOI

Salem J.H., 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. doi: 10.1016/j.procbio.2009.10.012. DOI

Fabre J., Betbeder D., Paul F., Monsan P., Perie J. Versatile enzymatic diacid ester: Synthesis of butyl delta-d-glucopyranoside. Tetrahedron. 1993;49:10877–10882. doi: 10.1016/S0040-4020(01)80240-4. DOI

McCabe R.W., Taylor A. An investigation of the acyl-binding site of Candida antarctica lipase B. Enzyme Microb. Technol. 2004;35:393–398. doi: 10.1016/j.enzmictec.2004.04.019. DOI

Ottolina G., Carrea G., Riva S. Regioselective enzymatic preparation of hemisuccinates of polyhydroxylated steroids. Biocatalysis. 1991;5:131–136. doi: 10.3109/10242429109014861. DOI

Bassanini I., Hult K., Riva S. Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers. Beilstein J. Org. Chem. 2015;11:1583–1595. doi: 10.3762/bjoc.11.174. PubMed DOI PMC

Magrone P., Cavallo F., Panzeri W., Passarella D., Riva S. Exploiting enzymatic regioselectivity: A facile methodology for the synthesis of polyhydroxylated hybrid compounds. Org. Biomol. Chem. 2010;8:5583–5590. doi: 10.1039/c0ob00304b. PubMed DOI

Theodosiou E., Loutrari H., Stamatis H., Roussos C., Kolisis F.N. Biocatalytic synthesis and antitumor activities of novel silybin acylated derivatives with dicarboxylic acids. New Biotechnol. 2011;28:342–348. doi: 10.1016/j.nbt.2011.01.006. PubMed DOI

Murota K., Matsuda N., Kashino Y., Fujikura Y., Nakamura T., Kato Y., Shimizu R., Okuyama S., Tanaka H., Koda T., et al. α-Oligoglucosylation of a sugar moiety enhances the biovailability of quercetin glucosides in humans. Arch. Biochem. Biophys. 2010;501:91–97. doi: 10.1016/j.abb.2010.06.036. PubMed DOI

Huang D.J., Ou B.X., Prior R.L. The chemistry behind antioxidant capacity assays. J. Agric. Food Chem. 2005;53:1841–1856. doi: 10.1021/jf030723c. PubMed DOI

Ziaullah, Bhullar K.S., Warnakulasuriya S.N., Rupasinghe H.P.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. doi: 10.1016/j.bmc.2012.11.034. PubMed DOI

Košinová P., Berka K., Wykes M., Otyepka M., Trouillas P. Positioning of antioxidant quercetin and its metabolites in lipid bilayer membranes: Implication for their lipid-peroxidation inhibition. J. Phys. Chem. B. 2011;116:1309–1318. doi: 10.1021/jp208731g. PubMed DOI

Mellou F., Lazari D., Skaltsa H., Tselepis A.D., Kolisis E., Stamatis H. Biocatalytic preparation of acylated derivatives of flavonoid glycosides enhances their antioxidant and antimicrobial activity. J. Biotechnol. 2005;116:295–304. doi: 10.1016/j.jbiotec.2004.12.002. PubMed DOI

Weignerová L., Marhol P., Gerstorferová D., Křen V. Preparatory production of quercetin-3-beta-d-glucopyranoside using alkali-tolerant thermostable α-l-rhamnosidase from Aspergillus terreus. Biores. Technol. 2012;115:222–227. doi: 10.1016/j.biortech.2011.08.029. PubMed DOI

Velioglu Y.S., Mazza G., Gao L., Oomah B.D. Antioxidant activity and total phenolics in selected fruits, vegetables and grain products. J. Agric. Food Chem. 1998;46:4113–4117. doi: 10.1021/jf9801973. DOI

Pyszková M., Biler M., Biedermann D., Valentová K., Kuzma M., Vrba J., Ulrichová J., Sokolová R., Mojovic M., Popovic-Bijelic A., et al. Flavonolignan 2,3-dehydroderivatives: Preparation, antiradical and cytoprotective activity. Free Radic. Biol. Med. 2016;90:114–125. doi: 10.1016/j.freeradbiomed.2015.11.014. PubMed DOI

Deby C., Magotteaux G. Essential fatty acids and antioxidizing substances in tissues of mouse. C. R. Séances Soc. Biol. Fil. 1970;164:2675–2681. PubMed

Joyeux M., Mortier F., Fleurentin J. Screening of antiradical, antilipoperoxidant and hepatoprotective effects of 9 plant-extracts used in caribbean folk medicine. Phytother. Res. 1995;9:228–230. doi: 10.1002/ptr.2650090316. DOI

Sulfated Metabolites of Flavonolignans and 2,3-Dehydroflavonolignans: Preparation and Properties

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Synthesis and Antiradical Activity of Isoquercitrin Esters with Aromatic Acids and Their Homologues