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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Synthesis and Biological Activity of Quercetin Derivatives ofEndogenous Opioid Peptides Leu- and Met-enkephalinAndreja Jakas 1 , Nina Bjeliš 1 , Ivo Piantanida 1 , and Marijeta Kralj 21 Rudjer Boskovic Institute, Division of Organic Chemistry and Biochemistry,10000, Zagreb, Croatia; 2 Rudjer Boskovic Institute, Division of Molecular Medicine,10000, Zagreb, CroatiaIntroductionQuercetin, 3,3',4',5,7-pentahydroxyflavone is well-known flavonoid distributed ubiquitouslyas a glycoside in fruits, vegetables and herbs (apples, onions, Ginkgo biloba) andrelated products, specially in red wine [1]. In plants, flavonoids are involved in energyproduction and exhibit strong anti-oxidant properties, possibly protecting plants againstharmful ultraviolet rays. Quercetin has become a subject of many investigations because ofstrong anti-cancer, anti-inflammatory, anti-oxidative and other therapeutic activities ofsignificant potency such as cardioprotective, bacteriostatic and nevertheless its systemictoxicity is quite low.On the other hand, it is known that the endogenous opioid peptides Leu- and Metenkephalin (Tyr-Gly-Gly-Phe-Leu/Met) acting as a cell growing factors have a role inanticancer activity as an inhibitor of cell division in a receptor-mediated fashion [2].Results and DiscussionThe goal of this study was to design and generate novel enkephalin analogs and to evaluatetheir anticancer activity. Taking in consideration that quercetin also has anticancer activity[3] prompted us to combine in the same molecule both quercetin and enkephalin in order toinvestigate their antitumor activity. Thus in the first stage, we carried out and determinedthe synthesis of coupling products between quercetin and Leu/Met-enkephalin as modelsystem.Figure 1 shows the pathway of derivatization of quercetin with protected Leu- andMet-enkephalin. Different protecting groups were used in the reaction in order to see theeffects on reactivity and selectivity in the formation of mono-, di- or penta-substitutedquercetine compound. Two condensation reagents, BOP and isobutylchloroformate, wereused, for preparation of the protected compounds.OHORHOOOHOHR'-Tyr(R')-Gly-Gly-Phe-Leu-OHOHOH O1a, 1b R=R'-Tyr-Gly-Gly-Phe-Leu-HOOOHOOH4 R=H-L-Tyr-Gly-Gly-L-Phe-L-Leu-5 R=H-L-Tyr-Gly-Gly-L-Phe-D-Leu-Boc-Tyr(Boc)-Gly-Gly-Phe-Leu-OHHOR'-Tyr(R')-Gly-Gly-Phe-Met-OHOHOROHOOOHOROHOH O2a, 2b R=R'-Tyr-Gly-Gly-Phe-Met-6 R=H-L-Tyr-Gly-Gly-L-Phe-L-Met-7 R=H-L-Tyr-Gly-Gly-L-Phe-D-Met-3a R=R'-Tyr-Gly-Gly-Phe-Leu-8 R=H-Tyr-Gly-Gly-Phe-Leu-R'a BocbZ-Fig. 1. Pathway of derivatization of quercetin with protected Leu-and Met–enkephalin.OHROOH322