title: Tetrapeptide tyrosine kinase inhibitors. Enantioselective synthesis of p-hydroxymethyl-L-phenylalanine, incorporation into a tetrapeptide, and subsequent elaboration into p-(R,S-hydroxyphosphonomethyl)-L-phenylalanine.
abstract: A convenient enantioselective synthesis of p-hydroxymethyl-L-phenylalanine was developed which produces a 4/1 ratio of L/D enantiomers resulting from a chiral phase-transfer-catalyzed alkylation. This amino acid was coupled into the p56(1)ck tyrosine kinase substrate Ac-Leu-Pro-Tyr-Ala-NHCH3 as a replacement for Tyr and can subsequently be elaborated into a variety of potential tyrosine kinase inhibitor designs of general structure Ac-Leu-Pro-AA-Ala-NHCH3, wherein AA is an unnatural amino acid. The contaminating D enantiomer was readily removed after coupling to L-Ala-NHCH3 of this sequence. The utility of the p-hydroxymethyl functionality in an efficient divergent synthetic strategy leading to various inhibitor designs is illustrated with the synthesis of Ac-Leu-Pro-AA-Ala-NHCH3, wherein AA is p-(R,S-hydroxyphosphonomethyl)-L-phenylalanine.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, SUNY at Buffalo.
authors.forename: M H
authors.initials: MH
authors.lastname: Kim
authors.forename: J H
authors.initials: JH
authors.lastname: Lai
authors.forename: D G
authors.initials: DG
authors.lastname: Hangauer
mesh_terms: D000595:Amino Acid Sequence; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D063065:Organophosphonates / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
chemical_list: C092681:4-hydroxyphosphonomethylphenylalanine; D009842:Oligopeptides; D063065:Organophosphonates; C092680:4-hydroxymethylphenylalanine; D010649:Phenylalanine; D011505:Protein-Tyrosine Kinases