Concise and enantioselective synthesis of Fmoc-Pmp(But)2-OH and design of potent Pmp-containing Grb2-SH2 domain antagonists.
[reaction: see text] L-Phosphonomethylphenylalanine (L-Pmp) is an important phosphatase-resistant pTyr analogue. A most concise and stereoselective approach to the synthesis of the suitably protected Fmoc-Pmp(Bu(t))(2)-OH was developed in order to incorporate the functionally significant L-Pmp residue into peptides and peptidomimetics efficiently using standard Fmoc protocol. With this key building block, we are able to efficiently synthesize a series of potent Pmp-containing Grb2-SH2 domain antagonists, which can be used as chemotherapeutic leads for the treatment of erbB2-overexpressed breast cancer.
Li
Peng
P
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
Zhang
Manchao
M
Peach
Megan L
ML
Liu
Hongpeng
H
Yang
Dajun
D
Roller
Peter P
PP
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D005449:Fluorenes / Q000737:chemistry; D051380:GRB2 Adaptor Protein; D020128:Inhibitory Concentration 50; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D019000:Phosphotyrosine / Q000031:analogs & derivatives; D011506:Proteins / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D005449:Fluorenes; D051380:GRB2 Adaptor Protein; D010456:Peptides, Cyclic; D010649:Phenylalanine; D019000:Phosphotyrosine; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C495949:Grb2 protein, mouse; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; C083973:4-phosphonomethylphenylalanine