Calixarene-based phosphinic acids as inhibitors of protein tyrosine phosphatases

Vladyslav M Buldenko; Viacheslav V Trush; Oleksandr L Kobzar; Andriy B Drapailo; Vitaly I Kalchenko; Andriy I Vovk

doi:10.1016/j.bmcl.2019.01.026

Calixarene-based phosphinic acids as inhibitors of protein tyrosine phosphatases

Bioorg Med Chem Lett. 2019 Mar 15;29(6):797-801. doi: 10.1016/j.bmcl.2019.01.026. Epub 2019 Jan 23.

Authors

Vladyslav M Buldenko¹, Viacheslav V Trush¹, Oleksandr L Kobzar¹, Andriy B Drapailo², Vitaly I Kalchenko³, Andriy I Vovk⁴

Affiliations

¹ V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Murmanska, 1, 02094 Kyiv-94, Ukraine.
² Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Murmanska, 5, 02094 Kyiv-94, Ukraine.
³ Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Murmanska, 5, 02094 Kyiv-94, Ukraine. Electronic address: vik@ioc.kiev.ua.
⁴ V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine, Murmanska, 1, 02094 Kyiv-94, Ukraine. Electronic address: vovk@bpci.kiev.ua.

PMID: 30704811
DOI: 10.1016/j.bmcl.2019.01.026

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 K_i value of 32 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.

Keywords: Calix[4]arene; Inhibition; Molecular docking; Phosphinic acids; Protein tyrosine phosphatase; Sulfonylcalix[4]arene; Thiacalix[4]arene.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calixarenes / chemical synthesis
Calixarenes / chemistry*
Calixarenes / metabolism
Catalytic Domain
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Humans
Kinetics
Molecular Docking Simulation
Phosphinic Acids / chemical synthesis
Phosphinic Acids / chemistry*
Phosphinic Acids / metabolism
Protein Binding
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / chemistry
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism

Substances

Enzyme Inhibitors
Phosphinic Acids
Calixarenes
PTPN1 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 1