A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors
| Autor: | A. Michael Downey, Naresh Singh Tulsi, Christopher W. Cairo |
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| Rok vydání: | 2010 |
| Předmět: |
Stereochemistry
Phenylalanine Clinical Biochemistry Organophosphonates Pharmaceutical Science Protein tyrosine phosphatase Tripeptide Biochemistry Binding Competitive chemistry.chemical_compound Drug Discovery Peptide synthesis Amino Acid Sequence Tyrosine Amino Acids Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Fluorenes Peptide analog biology Organic Chemistry Amino acid Enzyme binding chemistry Enzyme inhibitor biology.protein Molecular Medicine Protein Tyrosine Phosphatases |
| Zdroj: | Bioorganicmedicinal chemistry. 18(24) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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