‘Clickable’ 2,5-diketopiperazines as scaffolds for ligation of biomolecules: their use in Aβ inhibitor assembly?

Organic & Biomolecular Chemistry Pub Date: 2014-05-12 DOI: 10.1039/C4OB00541D

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.

Graphical abstract: ‘Clickable’ 2,5-diketopiperazines as scaffolds for ligation of biomolecules: their use in Aβ inhibitor assembly
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