A unique and rapid approach toward the efficient development of novel protein tyrosine phosphatase (PTP) inhibitors based on 'clicked' pseudo-glycopeptides.
There has been considerable interest in the development of protein tyrosine phosphatase (PTP) inhibitors since many of the PTP members are tightly associated with major human diseases including autoimmune disorders, diabetes and cancer. We report here a unique and rapid approach toward the development of novel PTP inhibitor entities based on triazolyl pseudo-glycopeptides. By employing microwave-accelerated Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC or 'click reaction'), a series of triazole-linked serinyl, threoninyl, phenylalaninyl and tyrosinyl 1-O-gluco- or galactosides have been efficiently synthesized in high yields within only ~30 min. Successive biological assay identified these glycopeptidotriazoles as favorable PTP1B and CDC25B inhibitors with selectivity over TCPTP, LAR, SHP-1 and SHP-2. Both the structural diversity of the amino acid (Ser, Thr, Phe and Tyr) introduced and the epimeric identity (Glc or Gal) on monosaccharide scaffold were determined to impact the corresponding inhibitory activity and selectivity. In addition, the benzylated sugar scaffold was demonstrated to act as a crucial role for enhancing the binding affinity of the inhibitors with the targeted PTP. Docking simulation was eventually conducted to propose plausible binding modes of this compound series with PTP1B and CDC25B. Our approach readily realized from naturally abundant raw materials (sugar and amino acid) and via facile, regioselective and expeditious synthetic method (microwave-assisted click reaction) might provide new insights toward the 'click' fabrication of structurally diverse PTP inhibitors.
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China.
Jin-Wei
JW
Yang
Xiao-Peng
XP
He
Cui
C
Li
Li-Xin
LX
Gao
Li
L
Sheng
Juan
J
Xie
Xiao-Xin
XX
Shi
Yun
Y
Tang
Jia
J
Li
Guo-Rong
GR
Chen
D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D057930:Click Chemistry; D003198:Computer Simulation; D003300:Copper / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006020:Glycopeptides / Q000737:chemistry; D006801:Humans; D008872:Microwaves; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000480:Alkynes; D001386:Azides; D004791:Enzyme Inhibitors; D006020:Glycopeptides; D003300:Copper; C517008:CDC25B protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases