Convergent synthesis of potent peptide inhibitors of the Grb2-SH2 domain by palladium catalyzed coupling of a terminal alkyne.
A new strategy was developed to prepare in a very efficient and convergent manner C-terminal modified tripeptides with high affinities for the Grb2-SH2 domain. Using Pd(PPh3)2Cl2 as catalyst, selected naphthyl iodides and triflates were coupled to Ac-Pmp(t-Bu)2-Ac6c-Asn-NH(prop-2-ynyl). The resulting alkyne derivatives were hydrogenated and deprotected to afford potent Grb2-SH2 inhibitors.
Schoepfer
J
J
Oncology, Research, NOVARTIS Pharma AG, Basel, Switzerland. joseph.schoepfer@pharma.novartis.com
Gay
B
B
End
N
N
Muller
E
E
Scheffel
G
G
Caravatti
G
G
Furet
P
P
D048868:Adaptor Proteins, Signal Transducing; D002384:Catalysis; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D051380:GRB2 Adaptor Protein; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010165:Palladium / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D018909:src Homology Domains / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D009842:Oligopeptides; D011506:Proteins; D010165:Palladium