title: Ring-closing metathesis of C-terminal allylglycine residues with an N-terminal beta-vinyl-substituted phosphotyrosyl mimetic as an approach to novel Grb2 SH2 domain-binding macrocycles.
abstract: 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 beta-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 beta-vinyl-functionalized phosphotyrosyl mimetic and C-terminal 2-allyl-3-aryl-1-propanamides that lacked the alpha-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.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute/NIH, Frederick, MD 21702, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Lakshman K
authors.initials: LK
authors.lastname: Bindu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000501:Allylglycine / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D003500:Cyclization; D051380:GRB2 Adaptor Protein; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis*; D018716:Molecular Mimicry; D015394:Molecular Structure; D019000:Phosphotyrosine / Q000737:chemistry*; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D047028:Macrocyclic Compounds; D000501:Allylglycine; D019000:Phosphotyrosine