Design and synthesis of 4-(alpha-hydroxymalonyl)phenylalanine as a new phosphotyrosyl mimetic and its use in growth factor receptor bound 2 src-homology 2 (Grb2 SH2) domain-binding peptides.
A new phosphotyrosyl mimetic 4-(alpha-hydroxymalonyl)phenylalanine and its incorporation into a Grb2 SH2 domain-binding tripeptide are presented. In whole-cell studies using malonyl ethyl ester prodrug derivatives, it was observed that the 4-(alpha-hydroxymalonyl)phenylalanyl-containing peptide exhibited greater efficacy than the nonhydroxylated 4-(malonyl)phenylalanyl-containing congener in blocking the association of Grb2 with activated erbB-2 tyrosine kinase. These results are consistent with de-esterification and at least partial intracellular decarboxylation.
Kang
Sang-Uk
SU
Laboratory of Medicinal Chemistry, CCR, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Worthy
Karen M
KM
Bindu
Lakshman K
LK
Zhang
Manchao
M
Yang
Dajun
D
Fisher
Robert J
RJ
Burke
Terrence R
TR
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D006801:Humans; D008314:Malonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019000:Phosphotyrosine / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D004952:Esters; D051380:GRB2 Adaptor Protein; D008314:Malonates; D009842:Oligopeptides; D010649:Phenylalanine; D019000:Phosphotyrosine; D011355:Prodrugs; D018719:Erb-b2 Receptor Tyrosine Kinases; C503906:4-(alpha-hydroxymalonyl)phenylalanine; C495948:GRB2 protein, human