Enantioselective synthesis of nonphosphorus-containing phosphotyrosyl mimetics and their use in the preparation of tyrosine phosphatase inhibitory peptides

Three new L-amino acid analogues 12, 18 and 25 have been prepared in protected form suitable for incorporation into peptides by solid-phase synthesis using Fmoc protocols. These agents represent nonphosphorus- containing phosphotyrosyl (pTyr) mimetics, which utilize carboxylic groups to provide functionality normally afforded by the pTyr phosphate group. To demonstrate the utility of these analogues, the protein-tyrosine phosphatase- directed peptides Ac-D-A-D-E-X-L-amide (28 - 30) were prepared, where X = pTyr mimetic. In the case where X = 3-carboxy-4-(O-carboxymethyl)-L-tyrosine (8) a K(i) value of 3.6 μM was obtained against PTP1, which equals the Km of the parent pTyr containing peptide. Besides tyrosine phosphatases, these analogues may be useful in a number of contexts, including SH2 domain and phosphotyrosine binding domain systems.