【文章名】Synthesis and Utilization of Chiral a-Methylated a-Amino Acids with a Carboxyalkyl Side Chain in the Design of Novel Grb2-SH2 Peptide Inhibitors Free of Phosphotyrosine.
Synthesis and Utilization of Chiral a-Methylated a-Amino Acids with a Carboxyalkyl Side Chain in the Design of Novel Grb2-SH2 Peptide Inhibitors Free of Phosphotyrosine.
[摘要]：The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-contg. docking module that represents an attractive target for anticancer therapeutic intervention. To improve the potency and bioavailability of the Grb2-SH2 inhibitors, the chiral a-methyl-a-carboxyalkyl amino acid [(a-Me)AA] was designed to cover dual structural and functional features sep. contributed by 1-aminocyclohexanecarboxylic acid (Ac6c) and a-aminoadipic acid (Adi) in position Y + 1. The enantiopure L(or D)-(a-Me)AA bearing various chain length carboxylalkyl side chain was conveniently synthesized by an optimized oxazolidinone methodol. The incorporation of (S)-(a-Me)AA into the non-pTyr-contg. peptide framework with a 5-amino acid sequence binding motif of X-2-Leu-(3'-substituted-Tyr) -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 mM). More significantly, these (a-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.
