Zhen-Dan Shi

Ring‐Closing Metathesis of C‐Terminal Allylglycine Residues with an N‐Terminal β‐Vinyl‐Substituted Phosphotyrosyl Mimetic as an Approach to Novel Grb2 SH2 Domain‐Binding Macrocycles

Ring‐closing metathesis (RCM) of peptides often requires insertion of allylglycines at the intended sites of ring juncture, which can result in the displacement of residues that are needed for biological activity. This type of side‐chain deletion can be avoided by appending β‐vinyl substituents onto the parent residues at the intended sites of ring juncture, thereby effectively converting them into functionalized allylglycine equivalents. Such an approach has been previously applied in modified form to growth‐factor receptor bound 2 (Grb2) SH2 domain‐binding peptides by using an N‐terminal β‐vinyl‐functionalized phosphotyrosyl mimetic and C‐terminal 2‐allyl‐3‐aryl‐1‐propanamides that lacked the α‐carboxyl portion of allylglycine residues. These C‐terminal moieties involved lengthy synthesis and once prepared, required an individual total synthesis of each final macrocycle. Work reported herein significantly enhances the versatility of the original approach through the use of C‐terminal allylglycine amides that can be prepared from commercially available L‐ and D‐allylglycines and suitable amines. This methodology could be generally useful where macrocylization is desired with maintenance of functionality at a site of ring juncture.

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

Introduction 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 β-bend conformations [1]. 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 AcpTyr-Ac6c-Asn-[3-(1-naphthyl)propylamide] reported by Novartis Corp [2], we had previously examined a number of monoanionic phosphoryl mimetics that exhibited micromolar to sub-micromolar Grb2 SH2 domain-binding affinities [3]. 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 [4] and 2 [5], 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).