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

• Published in: European journal of medicinal chemistry 2012-03, Vol.49, p.354-364
• Main Authors: Wang, Qingming, Zhu, Miaoli, Zhu, Ruiting, Lu, Liping, Yuan, Caixia, Xing, Shu, Fu, Xueqi, Mei, Yuhua, Hang, Qingwei
• Format: Article
• Language: English
• Subjects: Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Cell viability; Competitive inhibitor; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; Medical sciences; Miscellaneous; Models, Molecular; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Protein tyrosine phosphatases; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - metabolism; Selective inhibitor; α-Aminophosphonate
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.01.038

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. [Display omitted] ► 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.