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Table1. Structures and activities of selected BK antagonist peptidesNumberStructureGPI apA 2SCLC bin vitroBiological activitySHP-77 cin vivo (%)A-549 c,din vivo (%)PC3 c,ein vivo (%)B9430 8.2 120 15 42 Not activeB9870Suim-(B9430)28.4 0.15 65 58 78B10346 Sub-(B9430)2 -- 6 -- 40 --a Bradykinin antagonist activity (pA 2 ) on isolated guinea pig ileum (GPI)b IC 50 ( M) for cytotoxicity by MTT test for small cell lung cancer (SCLC) in vitro with cellline SHP-77c Per cent inhibition of growth of xenografts in nude mice. Compounds were injected i.p. at5 mg/kg/dayd Non-small cell lung cancer (NSCLC) cell line A-549e Prostate cancer (PC3)intended to create a potential anti-cancer bradykinin-antagonist peptide dimer prodrug.Prodrugs of bioactive amidine compounds have been investigated and some have advancedinto human clinical studies [9]. The stable bis-amide dimer, B10346, shows lower anticancerpotency than B9870. It is not clear whether this is the result of the inability of thebis-amide to undergo the degradation reactions of B9870. Whether due to its prodrugnature, i.e., the degradation process producing active derivatives, or otherwise, B9870 is apotent anti-cancer agent. The precise role of the degradation process in this context is underinvestigation.HNCB9430HNCB9430HNCB9430CH 2 6C NHPBSHN(R) OHC CB9598CH 2HN3C NH 2NHCH 2 6B9598 +C H 2OHN N(R)HC COCH 2HN3C NH 2NHCH 2 6C NHHN(R)HC COHOCH 2HN3C NH 2NHB9870B10660An IND application to test B9870 in small cell lung cancer was recently approved by theFDA and therefore the clinical trial can now proceed.References1. Gera, L., Stewart, J.M. Immunopharmacol. 33, 174-177 (1996).2. Gera, L., et al. Immunopharmacol. 33, 178-182 (1996).3. Chan, D.C., et al. Drug Resist. Updates 1, 377-388 (1998).4. Bernath, G., Toth, G., Fulop, F., Gondos, G., Gera, L. J.C.S. Perkin1 1765-1769 (1979).5. Wang, J., et al. J. Pharm. Biomed. Anal. 51, 824-833 (2010).6. Straub, J.A., Akiyama, A., Parmar, P., Musso, G.F. Pharmaceut. Res. 12, 305-308 (1995).7. Chan, D.C., Gera, L., et al. Immunopharmacol. 33, 201-204 (1996).8. Chan, D.C., Gera, L., et al. Clin. Cancer Res. 8, 1280-1287 (2002).9. Maryanoff, B.E., et al. Chem. Biol. Drug Des. 68, 29-36 (2006).309
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
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Peptides 2010Tales of PeptidesProce
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Peptides 2010Tales of PeptidesProce
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IntroductionWe had the distinct hon
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Scientific programIn planning the 3
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31 st EUROPEAN PEPTIDE SYMPOSIUMSep
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published by John Wiley & Sons as a
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The Josef Rudinger AwardThis award
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Young Investigators' SymposiumThe y
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xxiv
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Design of Peptidyl-Inhibitors for G
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Synthetic Antifreeze Glycopeptide A
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Synthesis and Oxidative Folding of
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Convergent Syntheses of Huprp106-12
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Bactericidal Activity of Small Beta
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Bradykinin Analogues Acylated on Th
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Antimicrobial Activity of Small 3-(
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Interaction of Curcumin with A-Synu
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Fluorescent and Luminescent Fusion
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Cellular Expression of the Human An
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2D IR Spectroscopy of Oligopeptides
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large, non-redundant subset of prot
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The aberrantly glucosylated peptide
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Table 1. Proline cis/trans ratios o
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Table 1. Yields, UV-vis absorption
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Table 1. Purity of the targeted tri
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processes are blocked. Interestingl
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(tb4 n ,1 m )MTII(tb1 n ,4 m )MTIIF
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Fig. 2. a) Part of the 400 MHz HR-M
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Once printed, the amino acid partic
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A) PSA, few seconds73B) PSA, 45 min
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short β strands. In contrast, nume
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neg. control Cs9-Rhd MM-218Fig. 2.
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Table 1. The general structure of t
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% ID in the liver 1 h p.i.100908070
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Peptidyl phosphoranes were first re
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obtained from the same sardines and
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MccJ25 variants were produced by si
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Fig. 2. Proposed signaling mechanis
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Table 1. mCD4-HS12 antiviral activi
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Subject index(S)-2-(1-adamantyl)gly
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chip 18chiral triazine condensing r
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heat stress 348helical conformation
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O-acyl isopeptide method 112obesity
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SH2-ligands 210short collagen-relat
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Author indexAboye, Teshome Leta 142
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Chi, Hongfang 480Chiche, Laurent 6C
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Geronikaki, Athina 444Gessmann, Ren
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Kostova, Kalina 528Kotzia, Georgia
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Nagata, Koji 162Nagayev, Igor Yu. 5
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Salvarese, Nicola 518Sammet, Benedi
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Vauquelin, Georges 138Veiga, Ana Sa
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