Exploration of α-aminophosphonate N-derivatives as novel, potent and selective inhibitors of protein tyrosine phosphatases.

Seventeen α-aminophosphonates are synthesized. Their compositions and structures are established by EA, UV, FT-IR, (1)H NMR, (13)C NMR, (31)P NMR and ESI-MS. Compounds 1-4 are confirmed by X-ray crystallography. PTP inhibition shows compounds 1-5, 12, 15 are moderate competitive inhibitors with some selectivity. The most potent inhibitor is compound 5 with the lowest IC(50) value about 6.64 μM against PTP1B, about 2-fold and 25-fold stronger than against TCPTP and PTP-MEG2 while it doesn't inhibit SHP-1 and SHP-2. The binding constant of 5 to PTP1B is 2.23 × 10(5) M(-1) and binding ratio approximates 1:1. Cell viability and apoptosis assays indicate 5 is cell permeable with lower cytotoxicity. The results indicate α-aminophosphonates are possibly developed to effective and selective inhibitors of PTPs. Copyright Â