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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, 2010Cyclic Peptides with a Diversely Substituted Guanidine Bridge:Synthesis, Structural and Biological Evaluations ofModel PeptidesYouness Touati Jallabe 1 , Engin Bojnik 2 , Laurent Chiche 3 ,Abdallah Hamzé 1 , André Aumelas 3 , Nga N. Chung 4 ,Peter W. Schiller 4 , Dorothée Berthomieu 5 , Sandor Benyhe 2 ,Vincent Lisowski 1 , Jean Martinez 1 , and Jean-François Hernandez 11 Institut des Biomolécules Max Mousseron, CNRS UM5247, Universités Montpellier 1 and2, Montpellier, 34093, France; 2 Institute of Biochemistry, Biological Research Center,Szeged, 6726, Hungary; 3 Centre de Biochimie Structurale, Montpellier, 34090, France;4 Laboratory of Chemical Biology and Peptide Research, Montreal, H2W 1R7, Canada;5 Institut Charles Gherardt, MACS, Montpellier, 34296, FranceIntroductionIn addition to occurring in numerous natural compounds, cyclization is often used inpeptide chemistry to generate peptides with higher stability, potency and selectivity, byconstraining the peptide backbone. Cyclization can be achieved through various bridgingbonds, between peptide ends and/or side-chains. In the later case, it mostly involves adisulfide bond, but there can be many other possibilities. But, once cyclized, these bridgesdo not allow further structural variation. We developed cyclized peptides with a diverselysubstituted guanidine bridge and showed using model peptides that this variability mightmodulate their conformation and biological activity.Results and DiscussionThe guanidine bridge is formed between the side-chains of two diaminoacyl residues andthe extra-cyclic nitrogen can be non- (R 1 , R 2 = H), mono- (R 1 = H, R 2 = Alk) or disubstituted(R 1 , R 2 = Alk). Their synthesis followed a convergent solid phase strategyHNXHNXOmMttNHOmHNPeptidePeptideSNHHNHNOnOnYNHYAlloc1) Pd(PPh 3) 42) DPT1) DCM/TFE/AcOH2) THF,70 C1) CH 3I2) HN R 1R 23) TFAScheme 1. Solid phase strategy.ccN N H HNR 1 R 2HNN HNR 1 R 2Fig. 1. c = cis, t = trans.HNXHNXHN NHNR 1 R 2OmMttNHOPeptideHNOOYHNPeptide YmnHN NR 1 NR 2tc ct ttHNnNR 1 R 2N C SHN(Scheme 1). First, a peptide containingtwo orthogonally protecteddiaminoacyl residues was assembledon a low loaded support. The allocgroup was then selectively removedand the free amino group wasconverted into isothiocyanate usingdi-(2-pyridyl)-thionocarbonate.After Mtt removal, intramolecularreaction afforded the cyclic peptidewith a thiourea bridge. Theguanidine bridge was obtained justbefore cleavage by treating the S-methyl intermediate with variousamines. LC-MS analyses showed that the major peak contained the expected compoundand that the main purity corresponded to a dimerisation product. The dimer proportion wasfound to decrease when decreasing the cycle size. Then, we were able in some case tolargely diminish this secondary species by adding LiCl in the cyclization mixture.With respect to its planarity, we anticipated that the guanidine bridge could adopt fourdifferent orientations inside the peptide cycle (Figure 1) and we hypothesized that thedegree of guanidine substitutionmight influence this orientation andtherefore peptide conformation. Aseries of proline-containing andRGD-related cyclic analogues ofvarious sizes and with a diverselysubstituted guanidine bridge wasprepared and studied by 2D-NMR6