6380 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Long et al.
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Nicklaus, M.; Roller, P. P. Potent Grb2-SH2 domain antagonists not
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Discovery of a novel non-phosphorylated pentapeptide motif displaying
high affinity for Grb2-SH2 domain by the utilization of 3′-substituted
tyrosine derivatives. J. Med. Chem. 2006, 49, 1585–1596.
(17) Rahuel, J.; Gay, B.; Erdmann, D.; Strauss, A.; GarciaEcheverria, C.;
Furet, P.; Caravatti, G.; Fretz, H.; Schoepfer, J.; Grutter, M. G.
Structural basis for specificity of Grb2-SH2 revealed by a novel ligand
binding mode. Nat. Struct. Biol. 1996, 3, 586–589.
(18) Ligand residues are numbered relative to the position of phosphoty-
rosine, or putative phosphotyrosine, which is denoted 0. Positive
numbers are used for amino acids C-terminal to phosphotyrosine, and
negative numbers are used for amino acids N-terminal to phospho-
tyrosine. In our case, the consensus sequence for binding to Grb2-
SH2 is YXN, in which Y is denoted 0.
(19) Furet, P.; Gay, B.; Caravatti, G.; Garcia-Echeverria, C.; Rahuel, J.;
Schoepfer, J.; Fretz, H. Structure-based design and synthesis of high
affinity tripeptide ligands of the Grb2-SH2 domain. J. Med. Chem.
1998, 41, 3442–3449.
(20) Liu, W. Q.; Vidal, M.; Gresh, N.; Rogues, B. P.; Garbay, C. Small
peptides containing phosphotyrosine and adjacent alpha mephospho-
tyrosine or its mimetics as highly potent inhibitors of Grb2 SH2
domain. J. Med. Chem. 1999, 42, 3737–3741.
(21) Liu, W.-Q.; Vidal, M.; Olszowy, C.; Million, E.; Lenoir, C.; Dhotel,
H.; Garbay, C. Structure-activity relationships of small phosphopep-
tides, inhibitors of Grb2 SH2 domain, and their prodrugs. J. Med.
Chem. 2004, 47, 1223–1233.
(22) Oishi, S.; Karki, R. G.; Kang, S.-U.; Wang, X.; Worthy, K. M.; Bindu,
L. K.; Nicklaus, M. C.; Fisher, R. J.; Burke, T. R., Jr. Design and
synthesis of conformationally constrained Grb2 SH2 domain binding
peptides employing R-methylphenylalanyl based phosphotyrosyl mi-
metics. J. Med. Chem. 2005, 48, 764–772.
N-Fmoc-Gla-Leu-(3′-NH2-Tyr)-Ac6c-Glu-Asn-amide (Peptide
19). ESI-MS m/z: calcd 943.4 (M - H)–, found 942.7. tR ) 13.6
min (10-70% of solvent B in 30 min, purity 99%); tR ) 21.0 min
(10-70% of solvent C in 30 min, purity 98%).
N-Fmoc-(R)-(r-Me)Adi-Leu-Tyr-Ac6c-Asn-amide (Peptide
20). ESI-MS m/z: calcd 912.6 (M + H)+, found 912.6. tR ) 19.25
min (10-90% of solvent B in 26 min, purity 99%); tR ) 21.8 min
(10-90% of solvent C in 27 min, purity 98%).
N-Fmoc-(S)-(r-Me)Adi-Leu-Tyr-Ac6c-Asn-amide (Peptide
21). ESI-MS m/z: calcd 912.6 (M + H)+, found 912.6. tR ) 19.75
min (10-90% of solvent B in 26 min, purity 99%); tR ) 21.6 min.
(10-90% of solvent C in 27 min, purity 97%).
N-Fmoc-(R)-(r-Me)Adi-Leu-(3′-NH2-Tyr)-Ac6c-Asn-amide
(Peptide 22). ESI-MS m/z: calcd 925.5 (M - H)–, found 925.3. tR
) 13.07 min (10-90% of solvent B in 26 min, purity 99%); tR )
19.7 min (10-90% of solvent C in 27 min, purity 98%).
N-Fmoc-(S)-(r-Me)Adi-Leu-(3′-NH2-Tyr)-Ac6c-Asn-amide
(Peptide 23). ESI-MS m/z: calcd 949.5 (M + Na)+, found 949.6.
tR ) 14.81 min (10-90% of solvent B in 26 min, purity 98%); tR
) 21.7 min (10-90% of solvent C in 27 min, purity 99%).
Acknowledgment. Appreciation is expressed to Prof. Xu
Shen and his colleagues of the DDDC at SIMM for the nice
assistance in our use of the Biacore 3000 instrument. This work
was supported by the funding from Chinese Academy of
Sciences (Grants KSCX2-YW-R-20 and KSCX2-YW-R-25) and
Ministry of Science and Technology of China (Grant
2004CB518903).
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