147108-45-0Relevant academic research and scientific papers
Conformational Studies on Peptides Containing Enantiomeric α-Methyl α-Amino Acids - Part I - Differential Conformational Properties of (R)- and (S)-2-Methylaspartic Acid
Altmann, Karl-Heinz,Altmann, Eva,Mutter, Manfred
, p. 1198 - 1210 (1992)
The conformational properties of four model peptides of the general formula Ac-Tyr-Xaa-Yaa-Zaa-Ala-Lys-Glu-Ala-Ala-Glu-Lys-Ala-Zaa-Yaa-Xaa-Lys-NH2 (Xaa-Yaa-Zaa = Ala-Ala-(R)-Asp(2-Me), 1; Ala-Ala-(S)-Asp(2-Me), 2; Ala-Aib-Asp, 3; Ala-Ala-Asp, 4; Asp(2-Me) = 2-methylaspartic acid; Aib = 2-aminoisobutyric acid) were studied by CD spectroscopy in solution, to evaluate the helix-inducing potential of enantiomerically pure 2-methylaspartic acid as a function of its chirality at C(2).At neutral pH and 1 deg C, all peptides exhibit significant helix formation in aqueous solution, the degree of helicity increasing in the order 4 3 ca. 2 1.Lowering the pH to 2 results in a dramatic increase in helicity for peptide 1, while the diastereoisomeric peptide 2 now exists in a predominantly unordered conformation.Helix induction by protonated (R)-Asp(2-Me) exceeds Aib-induced helix formation in peptide 3, and the helix content of 1 in aqueous solution at pH 2 is comparable to the degree of helicity in the strongly helix-inducing solvent 2,2,2-trifluoroethanol.
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.
