Synthesis of a 5-Methylindolyl-Containing Macrocycle That Displays Ultrapotent Grb2 SH2 Domain-Binding Affinity
- 13 January 2004
- journal article
- letter
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 47 (4) , 788-791
- https://doi.org/10.1021/jm030440b
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.Keywords
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