1231709-26-4Relevant articles and documents
Synthesis and utilization of chiral α-methylated α-amino acids with a carboxyalkyl side chain in the design of novel Grb2-SH2 peptide inhibitors free of phosphotyrosine
Long, Ya-Qiu,Xue, Ting,Song, Yan-Li,Liu, Zu-Long,Huang, Shao-Xu,Yu, Qiang
experimental part, p. 6371 - 6380 (2009/10/17)
The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. To improve the potency and bioavailability of the Grb2-SH2 inhibitors, the chiral α-methyl-α-carboxyalkyl amino acid [(α-Me)Aa] was designed to cover dual structural and functional features separately contributed by 1-aminocyclohexanecarboxylic acid (Ac6c) and α-aminoadipic acid (Adi) in position Y + 1. The enantiopure L(or D)-(α-Me)Aa bearing various chain length carboxylalkyl side chain was conveniently synthesized by an optimized oxazolidinone methodology. The incorporation of (S)-(α-Me)Aa into the non-pTyr-containing peptide framework with a 5-amino acid sequence binding motif of X-2-Leu- (3′-substituted-Tyr)0-X+1-Asn really improved the inhibitory activity, affording potent (R)-sulfoxide-bridged cyclic and an open-chain series of pentapeptide inhibitors of Grb2-SH2 domain (IC50 = 1.1-5.8 μM). More significantly, these (α-Me)Aa incorporated peptide inhibitors showed excellent activities in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with low micromolar IC50 values, owing to the reduced peptidic nature and absence of pTyr or pTyr mimetics.
