title: Synthesis of a 5-methylindolyl-containing macrocycle that displays ultrapotent Grb2 SH2 domain-binding affinity.
abstract: The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. Here, a ring-closing metathesis approach is utilized to synthesize a 5-methylindolyl-containing tetrapeptide mimetic (6) that exhibits unprecedented in vitro Grb2 SH2 domain-binding affinity (K(d) = 93 pM). Key to the preparation of 6 is the enantioselective synthesis of (2S)-2-(3-(5-methylindolyl)methyl)pent-4-enylamine (12) as one of two ring-closing segments.
authors.affiliation: Laboratory of Medicinal Chemistry, CCR, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Zhen-Dan
authors.initials: ZD
authors.lastname: Shi
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Wei
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Roberts
authors.forename: Karen M
authors.initials: KM
authors.lastname: Worthy
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fisher
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003500:Cyclization; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009842:Oligopeptides