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, 1H NMR, 13C NMR, 31P 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 IC50 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 × 105 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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► New α-aminophosphonates are synthesized and characterized. ► PTP inhibition assays show 5 potently and selectively inhibits PTP1B and TCPTP. ► Compound 5 is cell permeable with lower cytotoxicity.