Enantioselective synthesis of (S)-3-carboxy-4-((carboxy)difluoromethyl) phenylalanine in protected form and its incorporation into a PTP-1B-directed tripeptide

Sang Uk Kang, Yang Gao, Li Wu, Zhong-Yin Zhang, Terrence R. Burke

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 (F2Pmp). 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 α-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 pKa effects.

Original languageEnglish (US)
Pages (from-to)626-633
Number of pages8
JournalChemistry and Biodiversity
Volume1
Issue number4
DOIs
StatePublished - 2004
Externally publishedYes

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Halogenation
Phenylalanine
Fluorination
Peptides
Bearings (structural)
Amides
Amino Acids
Amino acids
Assays
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)
  • Bioengineering
  • Molecular Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Enantioselective synthesis of (S)-3-carboxy-4-((carboxy)difluoromethyl) phenylalanine in protected form and its incorporation into a PTP-1B-directed tripeptide. / Kang, Sang Uk; Gao, Yang; Wu, Li; Zhang, Zhong-Yin; Burke, Terrence R.

In: Chemistry and Biodiversity, Vol. 1, No. 4, 2004, p. 626-633.

Research output: Contribution to journalArticle

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