Structure-based design and solid-phase parallel synthesis of phosphorylated nonpeptides to explore hydrophobic binding at the Src SH2 domain

Using a novel, solid-phase parallel synthetic route and a computational doc king program, a series of phosphorylated nonpeptides were generated to dete rmine their structure-activity relationships (SAR) for binding at the SH2 d omain of pp60src (Src). A functionalized benzoic acid intermediate was atta ched to solid support via Rink amide linkage, which upon acid cleavage gene rated the desired benzamide template-based nonpeptides in a facile manner, Compounds were synthesized using a combination of solid- and solution-phase techniques. Purification using reversed-phase, semipreparative HPLC allowe d for quantitative SAR studies. Specifically, this work focused on function al group modifications, in a parallel fashion, designed to explore hydropho bic binding at the pY+3 pocket of the Src SH2 domain.