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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, 2010Structure-Activity Studies of Angiotensin IV AnaloguesContaining the Conformationally Constrained Aia ResidueIsabelle Van den Eynde 1 , Aneta Lukaszuk 1 , Koen Buysse 1 ,Heidi Demaegdt 2 , Philippe Karoyan 3 , Georges Vauquelin 2 ,Attila Keresztes 4 , Geza Toth 4 , Antal Péter 5 , and Dirk Tourwé 1Vrije Universiteit Brussel, 1 Department of Organic Chemistry; 2 Department of Molecularand Biochemical Pharmacology, Pleinlaan 2, B-1050, Brussels, Belgium, 3 CNRS/UMR7613, Université Pierre & Marie Curie, Place Jussieu 4, Paris, France, 4 Institute ofBiochemistry, Biological Research Center, Hungarian Academy of Sciences, 5 University ofSzeged, H-6701, Szeged, HungaryIntroductionAngiotensin IV: H-Val-Tyr-Ile-His-Pro-Phe-OH (Ang IV) is a physiological activemetabolite of Ang II in the renin-angiotensin system (RAS) [1]. At present it is clear thatAng IV and its analogues are effective at facilitating spatial learning [2], and have vascularand renal actions [3]. It was proposed that Ang IV may exertits effects through binding to AT4 receptors, also denoted asInsulin-Regulated Amino Peptidase (IRAP). We have reportedearlier that the β-homo-amino acid containing analog H-β 2 hVal-Tyr-Ile-His-Pro-β 3 hPhe-OH (AL-11) is a potent,selective and stable Ang IV antagonist, in which the β 2 hVal isresponsible for stability and the β 3 hPhe for selectivity [4]. Wealso reported an analogue (AL-40) in which the His 4 -Pro 5dipeptide residue is replaced by a constrained Trp residue,Aia-Gly (Figure 1).AL-40 has improved potency compared to the previouslyreported Al-11 [5]. In this study we replaced Gly 5 in AL-40 byAla, DAla, Pra, Nva or Gly 5 was deleted.Results and DiscussionSynthesis of Boc-(R)- β 2 -homo-Val:NHONHFig. 1. The Aia-Gly(R=H) scaffold.NRONOOH 2,Pd/CMeOH/HClquant.HClH .H 2NOO5N HClΔ84%26%ClH . H 2 NOH(R)OBoc 2 OK 2 CO 384%BocHNOOHClH . H 2 NHOHchiral column chromatographyO40%ClH . H 2 NOH(S) OScheme 1. Synthesis of Boc-(R) –β 2 -homo-Val.Ethyl-2-cyano-3-methylcrotonate was reduced by catalytic hydrogenation using 20wt%Pd/C (Johnson Mattey type 90) in MeOH/HCl in a Parr apparatus at 3.5 atm H 2 and 35°C.Ester hydrolysis was performed by refluxing overnight in 5N aqueous HCl. The obtainedrac-β 2 -homo-Val.HCl was resolved by semi preparative HPLC using a Chirobiotic Tagcolumn with 0.1M TEAA/MeOH (30/70) as eluent (Scheme 1).Peptide synthesis:Peptide synthesis was performed on Merrifield resin, using Boc protected amino acids. TheAia structure was build on resin by reductive amination of Boc-2-formyl-L-Trp and the free138