Abstract
A series of novel nonpeptide inhibitors of the pp60^c‐Src^ (Src) SH2 domain is described that exploit multifunctional group replacement of the phenylphosphate moiety of phosphotyrosine (pTyr). Relative to an x‐ray structure of citrate complexed to the pTyr binding site of the Src SH2 domain, these nonpeptide ligands illustrate the systematic replacement of the phosphate group by multiple nonhydrolyzable, mono‐ or dianionic functionalities. Specifically, several phenylalanine (Phe) analogs incorporating key 4′ and 3′ substituents were synthesized and incorporated into a bicyclic benzamide template previously reported (W. C. Shakespeare et al., Proceedings of the National Academy of Science USA , 2000, Vol. 97, pp. 9373–9378). These pTyr mimetics included 4′,3′‐diphosphono‐Phe (Dpp), 4′,3′‐dicarboxymethyloxy‐Phe (Dcp), and 4′‐phosphono‐3′‐carboxymethyloxy‐Phe (Cpp). Noteworthy were nonpeptide inhibitors 8–11 that were 5‐ to 10‐fold more potent than the cognate tetrapeptide ligand Ac–pTyr–Glu–Glu–Ile–NH~2~ in binding to the Src SH2 domain. © 2004 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2003