The design, synthesis and activity of pentapeptide pp60c-src inhibitors containing L-phosphotyrosine mimics.
Efficient syntheses of 4-(R,S-hydroxyphosphonomethyl)-L-phenylalanine and 4-carboxy-L-phenylalanine within the context of the pentapeptide Ac-Ile-X-Gly-Glu-Phe-NH2 (wherein X = the unnatural amino acid) illustrate the use of a divergent synthetic strategy from an advanced common peptide intermediate to more readily access peptide-based tyrosine kinase inhibitors. The key intermediate, Ac-Ile-Phe(4-formyl)-Gly-Glu(O-tBu)-Phe-NH2, was synthesized by a facile palladium-catalyzed carbonylation of Ac-Ile-Phe(4-iodo)-Gly-Glu(O-tBu)-Phe-NH2. Oxidation of Ac-Ile-Phe(4-formyl)-Gly-Glu(O-tBu)-Phe-NH2 with tetrabutylammonium permanganate or addition of di-t-butylphosphite, both followed by trifluoroacetic acid deprotection, gave the target pentapeptide inhibitors wherein X = 4-carboxy-L-phenylalanine or 4-(R,S-hydroxyphosphonomethyl)-L-phenylalanine, respectively. These two peptides gave somewhat more potent inhibition of the tyrosine kinase pp60c-src than the corresponding pentapeptide wherein X = L-phenylalanine, demonstrating that appended functionalities at the 4-position are accepted and can enhance binding through added interactions within the catalytic region of the active site.
Lai
J H
JH
Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo, USA. JLAI@bidmc.harvard.edu
Marsilje
T H
TH
Choi
S
S
Nair
S A
SA
Hangauer
D G
DG
D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D019000:Phosphotyrosine / Q000737:chemistry*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D019000:Phosphotyrosine; D016392:Proto-Oncogene Proteins pp60(c-src)