SYNTHESIS OF CONSTRAINED 4-(PHOSPHONOMETHYL)PHENYLALANINE DERIVATIVESAS HYDROLYTICALLY STABLE ANALOGS OF O-PHOSPHOTYROSINE

In order to elucidate the role of protein tyrosine phosphorylation inv olved in various intracellular signaling pathways, peptides containing O-phosphotyrosine have been developed. However, in order to improve t he stability of the phosphorylated amino acid we have designed some ye ars ago a hydrolytically stable analogue, the 4-(phosphonomethyl)pheny lalanine (Pmp). Introduced in peptide sequences, this residue, which i s resistant to phosphatase action, was shown also able to inhibit subs trate recognition by protein targets. With the aim to design peptidomi metics endowed with improved affinity and selectivity, we report in th is study the synthesis of five new sterically hindered amino acids der ived from Pmp. These modifications include alpha-methyl, beta-methyl b eta,beta-dimethyl substitutions, alpha,beta-cyclization of Pmp and met hyl substitution on the phosphonomethyl group of Pmp.