title: 'Clickable' 2,5-diketopiperazines as scaffolds for ligation of biomolecules: their use in Aβ inhibitor assembly.
abstract: The synthesis of 1,3,6-trisubstituted-2,5-diketopiperazine scaffolds bearing up to three 'clickable' sites for further oxime bond or alkyne-azide cycloaddition ligations is described. The orthogonally Boc/Alloc protected DKP precursors prepared from L-lysine residues and an aminohexyl arm are efficiently prepared on a gram scale by sequentially using Fukuyama-Mitsunobu alkylation, dipeptide coupling and diketopiperazine ring formation as key steps. These scaffolds, with their glyoxylyl, aminooxy, alkynyl or azido functions, are "ready-to-use" platforms for biomolecular assembly. Their potentiality in this field was proved through the chemoselective ligation of Aβ-binding motifs, the KLVFFA peptide and the curcumin molecule. The inhibitory effect of these conjugates on Aβ amyloid fibril formation is reported using thioflavin T fluorescence assays and AFM observation.
authors.affiliation: Département de Chimie Moléculaire, CNRS UMR 5250, ICMG FR 2607, Equipe I2BM, Université Joseph Fourier, 570 rue de la Chimie, BP 53, 38041 Grenoble cedex 09, France. sabine.chierici@ujf-grenoble.fr.
authors.forename: E
authors.initials: E
authors.lastname: Dufour
authors.forename: L
authors.initials: L
authors.lastname: Moni
authors.forename: L
authors.initials: L
authors.lastname: Bonnat
authors.forename: S
authors.initials: S
authors.lastname: Chierici
authors.forename: J
authors.initials: J
authors.lastname: Garcia
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D052160:Benzothiazoles; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D008026:Ligation; D013844:Thiazoles / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D054659:Diketopiperazines; D013844:Thiazoles; C009462:thioflavin T; D003474:Curcumin