RESUMEN
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.
Asunto(s)
Calixarenos/química , Inhibidores Enzimáticos/química , Ácidos Fosfínicos/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Calixarenos/síntesis química , Calixarenos/metabolismo , Dominio Catalítico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Cinética , Simulación del Acoplamiento Molecular , Ácidos Fosfínicos/síntesis química , Ácidos Fosfínicos/metabolismo , Unión Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismoRESUMEN
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.
RESUMEN
Thiacalix[4]arene 2, calix[4]arene 3a and its tetraether fixed in the cone conformation 3b form homo- and heterodimeric capsules in apolar solvents, which are held together by a seam of NH...O=P hydrogen bonds between carbamoylmethyl phosphine oxide functions attached to their wide rim. Their internal volume of approximately 370 A(3) requires the inclusion of a suitable guest. Although neutral molecules such as adamantane (derivatives) or tetraethylammonium cations form kinetically stable complexes ((1)H- and (31)P-time scale), the included solvent is rapidly exchanged. The internal mobility of the included tetraethylammonium cation is distinctly higher (DeltaG=42.5 and 49.7 kJ mol(-1) for 3a and 3b) than that for similar capsules of tetraurea calix[4]arenes 1. Mixtures of 1 with 2, 3a, or 3b contain only the two homodimers but the heterodimerization occurs with the tetraloop tetraurea 6, which cannot form homodimers. Two dimers with cationic guests (2.(C(5)H(5))(2)Co(+).2 and 3a.Et(3)NH(+).H(2)O.3a) were confirmed by single-crystal X-ray analysis.
RESUMEN
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.