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HO 2 CXY6a 3,5-diamino-6b 3-amino-4-hydroxy-6c 2-amino-5-hydroxy-6d 4-amino-2-hydroxy-HO 2 CCl-Trt chlorideresin, NMM,DMFa. (1) triphenylphosphine, DBAD,DCM, rt; (2) 3% TFA/DCMOaOOaHO 2 CNHHOXOH8a-dY(L)NHBocO4 (80%)5 (58%)NH(L)HOHOaNHBoc(L)NHBocNHMeaNHAllocHO 2 CHO 2 COONH9a (72%)RNHHN R3a (93%)HNHO 2 CHN3b (88%)ORRRHNOHO 2 CHHO 2 C NRO R3c (86%)3d (75%)R = (CH 2 ) 3 NHAllocRScheme 2: double hetero-M itsunobu solid phase synthesis of BBs 3a-d, 4,5,9aScheme 2. Double hetero-Mitsunobu solid phase synthesis of BBs 3a-d, 4, 5, 9a.corresponding aromatic amine can undergo Mitsunobu reaction. The Mitsunobu product2a was indeed obtained in good yields without further purification. Encouraged by thisresult, we proceded to the double heteroatom Mitsunobu reaction with a variety ofcommercially available disubstituted amino- and hydroxybenzoic acids 6a-d.Subsequently, in same manner as for 7 but with larger excess of reagents, thepreloaded 8a-d were submitted to the series of heteroatom couplings with functionalizedalcohols, yielding a unique collection of double armed dendron BBs 3a-d, 4, 5 and 9a(Scheme 2). These BBs vary by nature of the alkylated atom (oxygen or amine), armpositioning on the benzene ring, length, peripheral functional groups, protection andchirality (BBs 4, 5), demonstrating extended chiral diversification capabilities of aminoand hydroxybenzoic acids from easily accessible protected amino alcohols. We alsoexamined the tolerance of the Mitsunobu coupling reaction of alcohol synthons bearingunprotected aliphatic primary and secondary amines. Peripheral polyamines play animportant role in medicinal dendrimer science due to their solubility, ion salvationproperties, delivery and membrane permeability (PAMAM) [5]. Only an unprotectedsecondary amine was compatible with these conditions yielding unprotected 9a. Attemptsto optimize the reaction conditions, including microwave assisted chemistry, as well asimplementation of our dendron building blocks in convergent dendrimer evolution on solidsupport are in progress.AcknowledgmentsWe wish to thank Dr. Hugo Gotlib from Bar Ilan University for analytical assistance.References1. Gellerman, G., Shitrit, S., Shalit, T., Ganot, O., Albeck, A. Tetrahedron 66, 878-886 (2010).2. Swamy, K.K.C., Kumar, B.N.N, Pavan Kumar, K.V.P. Chem. Rev. 109, 2551-2651 (2009).3. Mitsunobu, O. Synthesis 1-28 (1981).4. Iranpoor, N., Firouzabadi, H., Khalili, H. Tetrahedron 65, 3893-3899 (2009).5. Majoros, I.J., Myc, A., Baker, J.R., Jr. Biomacromolecules 7, 572-579 (2006).225
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Peptidomimetic PKB/Akt Inhibitors as Anti-Cancer Drug LeadsYftah Tal-Gan 1 , Shoshana Klein 2 , Alexander Levitzki 2 ,and Chaim Gilon 11 Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel2 Unit of Cellular Signaling, Dept of Biological Chemistry, The Alexander SilbermanInstitute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904, IsraelIntroductionProtein Kinase B (PKB/Akt), a member of the Ser/Thr kinase family, is involved in cellproliferation and suppresses cell death (apoptosis). Persistently activated PKB/Akt isassociated with many types of human cancer, such as breast, colon, ovary, pancreas, headand neck, and prostate cancer. Inhibition of PKB/Akt is therefore an attractive strategy fortargeted cancer therapy. Screening of small molecules as enzyme inhibitors is verycommon. However, in the case of ATP-mimetic kinase inhibitors, the resulting smallmolecular weight inhibitors usually exhibit low selectivity towards the desired kinase,because kinase ATP-binding sites are strongly conserved. Substrate-based inhibitors,especially those based on the peptidic nature of the substrate, are more likely to beselective, because the substrate-binding site on each kinase is specific.Recently, a series of peptides derived from a PKB/Akt substrate – the proteinGlycogen Synthase Kinase 3 (GSK-3) – was developed and their interactions withPKB/Akt were studied [1]. The peptide Arg-Pro-Arg-Nva-Tyr-Dap-Hol (PTR6154), basedon the GSK-3 substrate peptide Arg-Pro-Arg-Thr-Ser-Ser-Phe, was found to be a selectivePKB/Akt inhibitor [1]. PTR6154 was used as a parent compound for this study. A libraryof peptomer derivatives of PTR6154 was produced and tested for inhibition of PKB/Akt.Results and DiscussionThe peptomers were named according to the modified residue (e.g. Peptomer 1 meansmodification on Arg 1). There are two synthetic pathways for solid phase peptomersynthesis: The first is based on reductive alkylation of glycine with the appropriatealdehyde or ketone to obtain the desired N α -alkylatedglycine derivative (Scheme 1a) [2]. The second methodis based on coupling of bromo-acetic acid to the freeamine of the growing peptide, followed by theintroduction of a primary amine bearing theappropriate alkyl side chain residue to obtain thedesired N α -alkylated glycine derivative (Scheme 1b),and is often referred to as the “sub-monomer” method[3]. Peptomers 4a, 5a and 7a (Table 1) weresynthesized, using readily available aldehydes andamines, by both methods for comparison. Nosignificant differences were detected between the twoScheme 1. Synthetic pathways for methods, either in yield or in product purity. InN α -alkylated glycine derivative: Peptomer 7a, a racemic HoIle peptomer building unita) using reductive alkylation. b) was incorporated instead of a Hol peptomer buildingusing the “sub-monomer” unit, for reasons of starting material availability. Inmethod. R – side chain, PG – order to synthesize Peptomers 1a and 3a (Table 1), weprotecting group.used the microwave assisted reductive alkylationprocedure of Park, et al. [4].The peptomer library was screened for inhibition of PKB/Akt in a cell-free radioactiveassay, and compared with PTR6154 [5]. The peptomer modification that was introducedled to a dramatic decrease in potency (Table 1). All of the peptomer analogs had negligiblepotency, and the “best” peptomers were still 10-fold less active than PTR6154. Theseresults suggest that the local constraints induced by the N α -alkylated glycine derivative, orthe inability of the backbone to produce the same number of hydrogen bonds as the parentPTR6154, reduced PKB/Akt inhibition.Our results indicate that the hydrogen bonds formed by the backbone have importantroles in site recognition and affinity to the enzyme. These results further suggest that226
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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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