Synthesis of a 5-Methylindolyl-Containing Macrocycle That Displays Ultrapotent Grb2 SH2 Domain-Binding Affinity

Zhen Dan Shi, Kyeong Lee, Chang Qing Wei, Lindsey R. Roberts, Karen M. Worthy, Robert J. Fisher, Terrence R. Burke

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Pages (from-to)788-791
Number of pages4
JournalJournal of Medicinal Chemistry
Volume47
Issue number4
DOIs
StatePublished - 12 Feb 2004

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