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

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• 作者：Ya-Qiu Long ; Ting Xue ; Yan-Li Song ; Zu-Long Liu ; Shao-Xu Huang ; Qiang Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 23, 2008
• 年：2008
• 卷：51
• 期：20
• 页码：6371-6380
• 全文大小：256K
• 年卷期：v.51,no.20(October 23, 2008)
• ISSN：1520-4804

文摘

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.