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 A c-Ile-X-Gly-Glu-Phe-NH2 (wherein X = the unnatural amino acid) illustr ate the use of a divergent synthetic strategy from an advanced common peptide intermediate to more readily access peptide-based tyrosine kin ase inhibitors. The hey intermediate, Ac-Ile-Phe(4-formyl)-Gly-Glu(O-t Bu)-Phe-NH2, was synthesized by a facile palladium-catalyzed carbonyla tion 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 permanga nate or addition of di-t-butylphosphite, both followed by trifluoroace tic acid deprotection, gave the target pentapeptide inhibitors wherein X = 4-carboxy-L-phenylalanine or 4-(R,S-hydroxyphosphonomethyl)-L-phe nylalanine, respectively. These two peptides gave somewhat more potent inhibition of the tyrosine kinase pp60(c-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. (C) Munksgaard 1998.