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Table 1. Analytical Data for Homobivalent Derivatives 3 and 4Compound Formula Calculated [ion] Found t R (purity)3 C 119 H 170 N 36 O 24 1244.6 [M+2H] 2+ 1244.6 15 min (98%)4 C 122 H 170 N 36 O 27 Re 920.6 [M+3H] 3+ 920.6 15.5 min (98%)The binding affinity of 3 (IC 50 = 0.33 ± 0.27 nM) to MC1R is very high and of the sameorder as NAPamide (IC 50 = 0.78 ± 0.03 nM) and the monovalent ligand pz-NAPamide(IC 50 = 0.66 ± 0.13 nM) prepared previously [3]. The metallation of 3 led to a complex 4with slightly lower affinity (IC 50 = 1.43 ± 1.54 nM).The radioactive complex 4a was prepared in high yield and radiochemical purity(98%) by reacting 3 with [ 99m Tc(CO) 3 (H 2 O) 3 ] + (Scheme 1). The highly hydrophiliccomplex 4a (log P o/w = - 1.82 ± 0.02) was characterized/identified comparing its RP-HPLCchromatogram with the one obtained for 4, synthesized as surrogate (Figure 1).ESI-MS[M+5H] 5+552.8[M+4H] 4+690.74a4[M+3H] 3+920.6Fig. 1. HPLC chromatograms of 4a (γ - detection)/ 4 (UV-vis detection) and ESI-MSspectrum of 4.In vitro studies have shown that 4a is stable in fresh human serum (6h, 37°C).Internalization studies in B16F1 murine melanoma cells revealed that over 45% of thecell-associated activity was internalized after 4 h, at 37°C.In conclusion, we have synthesized and characterized the novel homobivalentfac-[M(CO) 3 ] + complexes 4/4a (M = Re/ 99m Tc) containing the NAPamide. Preliminarystudies have shown that the radioactive complex is enzymatically stable, displayed highaffinity to MC1R and high cellular uptake. The biological evaluation of 4a in tumourbearingmice is currently underway.AcknowledgmentsM. Morais thanks FCT for a PhD grant (SFRH/BD/48066/2008). Covidean is acknowledged for theIsoLink ® Kits. Dr. J. Marçalo is acknowledged for performing the ESI-MS analyses. The QITMSinstrument was acquired with the support of the Programa Nacional de Reequipamento Científico(Contract REDE/1503/REM/2005 - ITN).References1. Miao, Y., Quinn, T. Crit. Rev. Oncol/Hematol. 67, 213-228 (2008).2. Raposinho, P.D., Correia, J.D.G., Cristina, M.C., Santos, I. Biopolymers: Peptide Science (2010).3. Raposinho, P.D., Correia, J.D.G., Alves, S., Botelho, M.F., Santos, A.C., Santos, I. Nucl. Med. Biol.35, 91-99 (2008).4. Vagner, J., Handl, H.L., Gillies, R., Hruby, V.J. Bioorg. Med. Chem. Lett. 14, 211-215 (2004).531
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Development of Drug Delivery Systems for Targeted CancerChemotherapy Based on GnRH Antagonist andAgonist PeptidesBence Kapuvári 1 , Borbála Vincze 1 , Marilena Manea 2 , Miguel Tejeda 1 ,Ákos Schulcz 1 , József Tóvári 1 , Dezső Gaál 1 , Erika Orbán 3 ,Ildikó Szabó 3 , and Gábor Mező 31 National Institute of Oncology, Budapest, Hungary; 2 University of Konstanz,Zukunftskolleg and Department of Chemistry, Laboratory of Analytical Chemistry andBiopolymer Structure Analysis, Konstanz, Germany; 3 Research Group of PeptideChemistry, Hungarian Academy of Sciences, Eötvös L. University, , Budapest, HungaryIntroductionTargeted cancer chemotherapy has been developed to overcome the drawbacks associatedwith the application of free anticancer drugs (e.g. lack of selectivity, toxic side effects,multi-drug resistance of cancer cells). Tumor targeting is achieved by conjugating achemotherapeutic agent to a targeting moiety which is directed to specific binding sites oncancer cells [1]. Gonadotropin releasing hormone (GnRH) receptor expression wasidentified on different types of tumors, such as breast, ovarian, colon, endometrial, prostate,renal, brain, pancreatic, melanomas and non-Hodgkin’s lymphomas [2].The aim of our work was to use GnRH agonist and antagonist peptides as targetingmoieties for the attachment of anticancer drugs. Bioconjugates in which thechemotherapeutic agent daunorubicin (Dau) was attached through an oxime bond to theGnRH analogs MI-1892 (Ac-wxwSkD(LQPa-NH 2 )-DEA, where x is D-p-chlorophenylalanine,DEA is diethylamide, and small letters mean D-amino acids) [3] and GnRH-III(
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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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Proceedings of the 31 st European P
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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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