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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 Evaluation of Cytotoxic PeptideConjugates Containing 5-FluorouracilSergey V. Burov, Tatyana V. Yablokova, Maria V. Leko,Anton Yu. Alenko, and Marina Yu. DoroshInstitute of Macromolecular Compounds, Russian Academy of Sciences,St. Petersburg, 199004, RussiaIntroductionThe efficiency of conventional cancer chemotherapy is limited by the lack of drugselectivity and significant toxicity to normal cells. Conjugation of cytotoxic drugs toreceptor-binding peptides is one of the promising approaches for their targeted delivery tocancer cells. 5-Fluorouracil (5-FU) is widely applied for the treatment of solid tumors, suchas breast, colorectal, and gastric cancers. However, apart from well-known side effects,5-FU undergoes rapid clearance in blood plasma and can not destroy the large number ofmalignant cells.There are many 5-FU derivatives, described in the literature and protocols useful forits attachment to macromolecular carriers, including a very elegant approach, suggested byD.A. Putnam [1]. However, their practical utility for the synthesis of cytotoxic peptideanalogues is still limited due to the insufficient stability or complexity of syntheticprocedure.Results and DiscussionAs a promising candidate for attachment of cytotoxic agent to peptide carrier we havechosen 5-fluorouracil-1-acetic acid or 1-carboxymethyl-5-fluorouracil (CMFU), synthesizedby M. Tada in 1975 as a result of 5-FU alkylation by chloroacetic acid [2]. This stablederivative possessed cytotoxic properties and now is widely applied for the conjugationwith different natural compounds in order to improve its anticancer activity and selectivityof action.In 1990 we described truncated GnRH analogues containing CMFU moiety [3].Corresponding peptides were synthesized using CMFU-ONP derivative possessed veryhigh activity in amino group acylation reaction. However, biological experiments revealedthat antitumor action of tested analogues in vivo is relatively low due to the stronginfluence of cytotoxic moiety on their hormonal activity and binding to GnRH receptors.Considering these data we synthesized a set of GnRH analogues (I)-(VIII) whichdiffer by presence or absence of CMFU moiety, N-terminal modification and the structureof linker between peptide and cytotoxic agent (Figure 1).Ac-Pro-D-Phe-Pro-Ser-Tyr-D-Lys-Leu-Arg-Pro-Gly-NH 2(I)Ac-Pro-D-Phe-Pro-Ser-Tyr-D-Lys(CMFU)-Leu-Arg-Pro-Gly-NH 2 (II)Pam-Pro-D-Phe-Pro-Ser-Tyr-D-Lys-Leu-Arg-Pro-Gly-NH 2(III)Pam-Pro-D-Phe-Pro-Ser-Tyr-D-Lys(CMFU)-Leu-Arg-Pro-Gly-NH 2 (IV)CMFU-Pro-D-Phe-Pro-Ser-Tyr-D-Lys(CMFU)-Leu-Arg-Pro-Gly-NH 2 (V)pGlu-His-Trp-Ser-Tyr-D-Lys-Leu-Arg-Pro-Gly-NH 2(VI)pGlu-His-Trp-Ser-Tyr-D-Lys(CMFU)-Leu-Arg-Pro-Gly-NH 2 (VII)pGlu-His-Trp-Ser-Tyr-D-Lys(X-CMFU)-Leu-Arg-Pro-Gly-NH 2 (VIII)Lev-Arg-Gly-Asp-Phe-OH (IX)Pyv-Arg-Gly-Asp-Phe-OH (X)CMFU-X-Arg-Gly-Asp-Phe-OH (XI)O O OHHNNO N NFCMFU-XFig. 1. Synthesized GnRH analogs and model RGD peptides.310