The design, synthesis and activity of pentapeptide pp60(c-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 pp60(c- arc) 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.