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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 Studies of Cyclolinopeptide A AnalogsModified with 4-Substituted-PhenylalanineK. Kierus 1 , K. Ciupińska 1 , M. Waśkiewicz 1 , M. Grabowska 1 ,K. Kaczmarek 1 , J. Olejnik 1 , M. Zimecki 2 , S. Jankowski 1 ,and J. Zabrocki 1,31 Institute of Organic Chemistry, Technical University of Łódź, 90-924 Lodz, Poland;2 Institute of Immunology and Experimental Therapy, Polish Academy of Science,53-114, Wrocław, Poland; 3 Peptaderm Inc., Krakowskie Przedmieście Str. 13,00-071, Warsaw, PolandIntroductionImmunosuppressors are used in the medical praxis to prevent graft rejection after organtransplantation and in the therapy of some autoimmune diseases. Cyclolinopeptide A(CLA) (1), a cyclic, hydrophobic nonapeptide isolated from linseed (Figure 1), possessesstrong immunosuppressive and antimalarial activity [1]. It is postulated that both thePro-Pro cis-amide bond [2] and an „edge-to-face‟ interaction between the aromatic rings oftwo adjacent Phe residues [3] are important for biological activity. Since the „edge-to-face‟interaction can be modulated by electron withdrawing orelectron donating substituent in aromatic rings, we presentin this communication cyclic CLA analogues 2-9 in whichphenylalanine residues in positions 3 and 4 have beenreplaced with para-nitro-phenylalanine 10, para-aminophenylalanine11 and para-acetamido-phenylalanine 12(Figure 2).(2) c(P 1 -P 2 -(p-NO 2 )F 3 -F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)(3) c(P 1 -P 2 -F 3 -(p-NO 2 )F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)(4) c(P 1 -P 2 -(p-NO 2 )F 3 -(p-NO 2 )F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)(5) c(P 1 -P 2 -(p-NH 2 )F 3 -F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)(6) c(P 1 -P 2 -F 3 -(p-NH 2 )F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)(7) c(P 1 -P 2 -(p-AcNH)F 3 -F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)(8) c(P 1 -P 2 -F 3 -(p-AcNH)F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)Fig. 1. Cyclolinopeptide A (1). (9) c(P 1 -P 2 -(p-AcNH)F 3 -(p-AcNH)F 4 -L 5 -I 6 -I 7 -L 8 -V 9 -)Fig. 2. Para-nitro-phenylalanine (10),para-amino-phenylalanine (11) andpara-acetamido-phenylalanine (12).Scheme 1. Synthesis of Boc protected para-acetamidophenylalanine12.Results and DiscussionThe linear analogs of peptides 2-4 and 7-9 weresynthesized in 0.2 mmol scale by the manual solidphasemethod using chloromethylated Merrifieldresin as a solid support. Attachment of the firstBoc-AA-OH (Boc-Phe-OH or Boc-(pNO2)Phe-OHor Boc-(pAcNH)Phe-OH) to the resin wasperformed according to cesium salt procedure [4].The substitution level was determined around 0.60mg/g. Standard N-Boc-protected amino acids andBoc-p-NO 2 Phe-OH 13 were obtained fromcommercial sources. Another modified aminoacid 14 (Boc-(pAcNH)Phe-OH) wasobtained from Boc-(pNO 2 )Phe-OHin two steps synthesis: the reductionusing hydrogenolysis procedure andsubsequent acylation with acetylanhydride in presence of N-methylmorpholine(Scheme 1).The crude linear peptides werecyclized by means HOBt/EDC/DIPEA in DCM at much lower106