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.
Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of the Education Ministry, Shanxi University, Taiyuan, Shanxi, People's Republic of China.
Qingming
Q
Wang
Miaoli
M
Zhu
Ruiting
R
Zhu
Liping
L
Lu
Caixia
C
Yuan
Shu
S
Xing
Xueqi
X
Fu
Yuhua
Y
Mei
Qingwei
Q
Hang
D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000588:Amines; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D017027:Protein Tyrosine Phosphatases