title: Enantioselective synthesis of (S)-3-carboxy-4-((carboxy)difluoromethyl)phenylalanine in protected form and its incorporation into a PTP-1B-directed tripeptide.
abstract: Recent findings have shown that, when expressed in the tripeptide platform, 'Fmoc-Glu-Xxx-Leu-amide', the phosphotyrosyl mimetic (pTyr), Xxx=(S)-3-carboxy-4-(carboxymethyl)-Phe, provides higher PTP-1B affinity than that obtained with Xxx=(S)-difluorophosphonomethyl-Phe (F(2)Pmp). This was of note, since difluorophosphonomethyl-containing pTyr mimetics have typically exhibited higher PTP-inhibitory potencies than carboxy-based mimetics, indicating the potential value of 3-carboxy-4-(carboxymethyl)-Phe as a starting point for further analogue development. Therefore, relying on precedence that alpha-fluorination often enhances PTP-1B affinity, (S)-3-carboxy-4-((carboxy)difluoromethyl)-Phe was designed as a PTP-1B-directed pTyr mimetic. Reported herein is the synthesis of this new amino acid analogue through application of commercially available Williams chiral auxiliary. The target was prepared in an orthogonally protected form suitable for peptide synthesis according to Fmoc chemistries and utilization for the synthesis of a PTP-1B-directed tripeptide bearing the sequence indicated above. Biological evaluation with in vitro PTP-1B assays indicated nearly total loss of affinity for this peptide. Evidence is provided that the unexpected deleterious effect of fluorination is probably not related to pK(a) effects.
authors.affiliation: Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI, NIH, P.O. Box B, Bldg. 376 Boyles St., Frederick, MD 21702-1201, USA.
authors.forename: Sang Uk
authors.initials: SU
authors.lastname: Kang
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D001665:Binding Sites / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism; D010649:Phenylalanine / Q000138:chemical synthesis* / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000138:chemical synthesis* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D009842:Oligopeptides; D010649:Phenylalanine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases