Application of Phenylphosphate Mimetics to the Design and Synthesis of Olefin Metathesis-Derived Grb2 SH2 Domain-Binding Macrocycles

摘要

The growth factor receptor bound protein 2 (Grb2) is an SH2 domain-containing component of signaling pathways associated with a variety of proliferative diseases. Grb2 SH2 domains preferentially recognize sequences of the form, "pTyr-Xxx-Asn", with binding occurring in type-I beta-bend conformations. Significant research has been devoted to developing Grb2 SH2 domain-binding peptides and peptide mimetics as potential therapeutics. One aspect of these efforts has been directed toward overcoming bioavailability issues raised by the dianionic phenylphosphate moiety of pTyr. Using an open-chain display platform based on the peptide Ac-pTyr-Ac_6c-Asn-[3-(l-naphthyl)propylamide] reported by Novartis Corp, we had previously examined a number of monoanionic phosphoryl mimetics that exhibited micromolar to sub-micromolar Grb2 SH2 domain-binding affinities. More recently, we reported macrocyclic variants of the Novartis peptide bearing dianionic phosphoryl replacements that provide low nanomolar to sub-nanomolar binding constants (analogs 1 and 2, X = a and b, Fig. 1). The focus of the current; study was to examine phosphoryl mimicking groups bearing monoanionic charge (X = c,d,e and f) or no charge (X = g and h) within a macrocyclic platform (Fig. 1).