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 A beta-binding motifs, the KLVFFA peptide and the curcumin molecule. The inhibitory effect of these conjugates on A beta amyloid fibril formation is reported using thioflavin T fluorescence assays and AFM observation.
'Clickable' 2,5-diketopiperazines as scaffolds for ligation of biomolecules: their use in Ab inhibitor assembly
MONI, LISA;
2014-01-01
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 A beta-binding motifs, the KLVFFA peptide and the curcumin molecule. The inhibitory effect of these conjugates on A beta amyloid fibril formation is reported using thioflavin T fluorescence assays and AFM observation.
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