ABSTRACT
In the present work, the derivatives of calix[4]arene, thiacalix[4]arene, and sulfonylcalix[4]arene bearing four methylene(phenyl)phosphinic acid groups on the upper rim of the macrocycle were synthesized and studied as inhibitors of human protein tyrosine phosphatases. The inhibitory capacities of the three compounds towards PTP1B were higher than those for protein tyrosine phosphatases TC-PTP, MEG1, MEG2, and SHP2. The most potent sulfonylcalix[4]arene phosphinic acid displayed Ki value of 32â¯nM. The thiacalix[4]arene phosphinic acid was found to be a low micromolar inhibitor of PTP1B with selectivity over the other PTPs. The kinetic experiments showed that the inhibitors compete with the substrate for the active site of the enzyme. Molecular docking was performed to explain possible binding modes of the calixarene-based phosphinic inhibitors of PTP1B.
Subject(s)
Calixarenes/chemistry , Enzyme Inhibitors/chemistry , Phosphinic Acids/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Calixarenes/chemical synthesis , Calixarenes/metabolism , Catalytic Domain , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Kinetics , Molecular Docking Simulation , Phosphinic Acids/chemical synthesis , Phosphinic Acids/metabolism , Protein Binding , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolismABSTRACT
New properties, earlier unknown for calixarenes, were found for tert-butylthiacalix[4]arene (1) clathrate with 1,2-dichloroethane (DCE). Guest exchange in 1·1.90DCE for vapors of some organic compounds gives clathrates, which are more thermostable at 34-59 °C than those prepared by direct saturation of guest-free 1 with pure guests. Besides, guest exchange may produce clathrates that cannot be formed by direct saturation in binary host-guest systems. Some compounds, like water, toluene, and trichloroethylene, expel DCE from its clathrate with 1 but are not included above the trace level. Residual contents of DCE in clathrate may be controlled by variation of water and 1·1.90DCE ratio in the studied system. Host 1 can remember methanol after its elimination from the guest exchange product. This memory can be read as an exoeffect by differential scanning calorimetry. Only methanol and only after guest exchange is remembered giving an example of a genuine molecular recognition.
ABSTRACT
Inhibition of Yersinia protein tyrosine phosphatase by calix[4]arene mono-, bis-, and tetrakis(methylenebisphosphonic) acids as well as calix[4]arene and thiacalix[4]arene tetrakis(methylphosphonic) acids have been investigated. The kinetic studies revealed that some compounds in this class are potent competitive inhibitors of Yersinia PTP with inhibition constants in the low micromolar range. The binding modes of macrocyclic phosphonate derivatives in the enzyme active center have been explained using computational docking approach. The results obtained indicate that calix[4]arenes are promising scaffolds for the development of inhibitors of Yersinia PTP.
