Synthesis of constrained 4-(phosphonomethyl)phenylalanine derivatives as hydrolytically stable analogs of O-phosphotyrosine

Wang-Qing Liu , François Carreaux (1) , Hervé Meudal , Bernard P. Roques , Christiane Garbay-Jaureguiberry

1 Pharmacochimie moléculaire et structurale

In order to elucidate the role of protein tyrosine phosphorylation involved in various intracellular signaling pathways, peptides containing O-phosphotyrosine have been developed. However, in order to improve the stability of the phosphorylated amino acid, we have designed some years ago a hydrolytically stable analogue, the 4-(phosphonomethyl)phenylalanine (Pmp). Introduced in peptide sequences, this residue, which is resistant to phosphatase action, was shown also able to inhibit substrate recognition by protein targets. With the aim to design peptidomimetics endowed with improved affinity and selectivity, we report in this study the synthesis of five new sterically hindered amino acids derived from Pmp. These modifications include α-methyl, β-methyl, β,β-dimethyl substitutions, α,β-cyclization of Pmp and methyl substitution on the phosphomomethyl group of Pmp.

Domaines: Sciences du Vivant [q-bio]

Wang-Qing Liu, François Carreaux, Hervé Meudal, Bernard P. Roques, Christiane Garbay-Jaureguiberry. Synthesis of constrained 4-(phosphonomethyl)phenylalanine derivatives as hydrolytically stable analogs of O-phosphotyrosine. Tetrahedron, 1996, 52 (12), pp.4411-4422. ⟨10.1016/0040-4020(96)00085-3⟩. ⟨hal-02122054⟩