A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors

• Published in: Bioorganic & medicinal chemistry 2010-12, Vol.18 (24), p.8679-8686
• Main Authors: Tulsi, Naresh S., Downey, A. Michael, Cairo, Christopher W.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acids; Binding, Competitive; Biological and medical sciences; CD45; Enzyme Inhibitors - chemical synthesis; Fluorenes; Immunomodulators; Irreversible inhibitor; Medical sciences; Organophosphonates; Peptide analog; Peptide synthesis; Pharmacology. Drug treatments; Phenylalanine - analogs & derivatives; Phenylalanine - chemistry; Phosphatases; Phosphopeptide; Protein Tyrosine Phosphatases - antagonists & inhibitors; PTP
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.09.040

Protein tyrosine phosphatases (PTPs) are important therapeutic targets for medicinal chemists and biochemists. General strategies for the development of inhibitors of these enzymes are needed. Several modular strategies which rely on phosphotyrosine mimics are known for PTP inhibitors. Previous strategies include phosphonomethylphenylalanine (Pmp) derivatives which act as competitive inhibitors. Pmp amino acid derivatives have been used to develop specific inhibitors by incorporation into sequences recognized by the PTP of interest. We report the synthesis of a new phosphonotyrosine analog, l-phosphonobromomethylphenylalanine (BrPmp), which acts as an inhibitor of PTPs. The BrPmp derivative was prepared as an Fmoc-protected amino acid which can be used in standard solid phase peptide synthesis (SPPS) methods. The synthesis of the protected amino acid derivative requires 11 steps from tyrosine with a 30% overall yield. Enzyme inhibition studies with the PTP CD45 demonstrate that BrPmp derivatives are irreversible inhibitors of the enzyme. A tripeptide which incorporated BrPmp had increased inhibitory potency against PTP relative to BrPmp alone, confirming that the incorporation of BrPmp into peptide sequences provides additional context to improve enzyme binding.