A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors.
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.
Alberta Ingenuity Centre for Carbohydrate Science, Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Naresh S
NS
Tulsi
A Michael
AM
Downey
Christopher W
CW
Cairo
D000595:Amino Acid Sequence; D000596:Amino Acids; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005449:Fluorenes; D063065:Organophosphonates; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
D000596:Amino Acids; D004791:Enzyme Inhibitors; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D063065:Organophosphonates; D010649:Phenylalanine; D017027:Protein Tyrosine Phosphatases