The assessment of sulfonylcalix[4]arene derivatives as inhibitors of protein tyrosine phosphatases


  • V. M. Buldenko Institute of Bioorganic Chemistry and Petrochemistry of NAS of Ukraine, Ukraine
  • V. V. Trush Institute of Bioorganic Chemistry and Petrochemistry of NAS of Ukraine, Ukraine
  • O. L. Kobzar Institute of Bioorganic Chemistry and Petrochemistry of NAS of Ukraine, Ukraine
  • A. B. Drapailo Institute of Organic Chemistry of the NAS of Ukraine, Ukraine
  • S. G. Vyshnevsky Institute of Organic Chemistry of the NAS of Ukraine, Ukraine
  • V. I. Kalchenko Institute of Organic Chemistry of the NAS of Ukraine, Ukraine
  • A. I. Vovk Institute of Bioorganic Chemistry and Petrochemistry of NAS of Ukraine, Ukraine



sulfonylcalix[4]arene, protein tyrosine phosphatase, inhibition, molecular docking, molecular dynamics


Aim. To compare sulfonylcalix[4]arene derivatives containing ionizable or non-ionizable substituents at the upper rim of the macrocycle as inhibitors of protein tyrosine phosphatase 1B (PTP1B) and other PTPs.
Results and discussion. The properties of sulfonylcalix[4]arene with four phosphonic acid groups introduced at the upper rim were compared with those of the macrocycles containing four non-ionizable tert-butyl or trifluoroacetamide functions. The sulfonylcalix[4]arene tetrakis-methylphosphonic acid was found to inhibit PTP1B with IC50 value in the low-micromolar range without selectivity over other PTPs, such as TC-PTP, MEG1, MEG2, SHP2, and PTPβ. At the same time, modification of sulfonylcalix[4]arene with trifluoroacetamide substituents led to inhibition of PTP1B with IC50 of 1.4 μM and 4- to 28 fold selectivity over the other PTPs. In order to understand the ability of inhibiting PTP1B by sulfonylcalix[4]arene with introduced trifluoroacetamide groups the molecular docking and molecular dynamic simulations were performed. The inhibition mechanism was discussed.
Experimental part. The activities of the test compounds in vitro were examined spectrophotometrically measuring the rate of hydrolysis of p-nitrophenyl phosphate as a substrate of PTPs. The molecular docking was performed by AutoDock Vina.
Conclusions. This study can start an approach to develop new inhibitors of PTPs by variations in the nonionogenic substituents on the upper rim of sulfonylcalix[4]arene scaffold.

Author Biography

V. M. Buldenko, Institute of Bioorganic Chemistry and Petrochemistry of NAS of Ukraine

Відділ №3, інженер ІІ категорії, аспірант


Cohen, P. (2000). The regulation of protein function by multisite phosphorylation – a 25 year update. Trends in Biochemical Sciences, 25(12),


Hunter, T. (2000). Signaling—2000 and Beyond. Cell, 100(1), 113–127.

Zhang, Z.-Y. (2001). Protein tyrosine phosphatases: prospects for therapeutics. Current Opinion in Chemical Biology, 5(4), 416–423. https://

Tonks, N. K. (2013). Protein tyrosine phosphatases - from housekeeping enzymes to master regulators of signal transduction. FEBS Journal,

(2), 346–378.

He, R., Yu, Z., Zhang, R., & Zhang, Z. (2014). Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacologica Sinica, 35(10),


Mandolini, L., Ungaro, R. (2000). Calixarenes in Action. World Scientific Pub. Co.

Joseph, R., & Rao, C. P. (2011). Ion and Molecular Recognition by Lower Rim 1,3-Di-conjugates of Calix[4]arene as Receptors. Chemical Reviews,

(8), 4658–4702.

Naseer, M. M., Ahmed, M., & Hameed, S. (2017). Functionalized calix[4]arenes as potential therapeutic agents. Chemical Biology & Drug Design,

(2), 243–256.

Molenveld, P., Engbersen, J. F. J., & Reinhoudt, D. N. (2000). Dinuclear metallo-phosphodiesterase models: application of calix[4]arenes as molecular

scaffolds. Chemical Society Reviews, 29(2), 75–86.

Casnati, A., Sansone, F., & Ungaro, R. (2003). Peptido- and Glycocalixarenes: Playing with Hydrogen Bonds around Hydrophobic Cavities. Accounts of Chemical Research, 36(4), 246–254.

Giuliani, M., Morbioli, I., Sansone, F., & Casnati, A. (2015). Moulding calixarenes for biomacromolecule targeting. Chemical Communications,

(75), 14140–14159.

Trush, V. V., Cherenok, S. O., Tanchuk, V. Y., Kukhar, V. P., Kalchenko, V. I., & Vovk, A. I. (2013). Calix[4]arene methylenebisphosphonic acids as inhibitors of protein tyrosine phosphatase 1B. Bioorganic & Medicinal Chemistry Letters, 23(20), 5619–5623.

Trush, V. V., Kharchenko, S. G., Tanchuk, V. Y., Kalchenko, V. I., & Vovk, A. I. (2015). Phosphonate monoesters on a thiacalix[4]arene framework as potential inhibitors of protein tyrosine phosphatase 1B. Organic & Biomolecular Chemistry, 13(33), 8803–8806.

Buldenko, V., Kobzar, O., Trush, V., Drapailo, A., … Kalchenko, V. (2017). Sulfonyl-bridged Calix[4]arene as an Inhibitor of Protein Tyrosine Phosphatases.

French-Ukrainian Journal of Chemistry, 5(2), 144–151.

Gutsche, C. D. (2008). Calixarenes: an introduction. Royal Society of Chemistry, 10.

Barford, D., Flint, A., & Tonks, N. (1994). Crystal structure of human protein tyrosine phosphatase 1B. Science, 263(5152), 1397–1404. https://

Montalibet, J., Skorey, K., McKay, D., Scapin, G., Asante-Appiah, E., & Kennedy, B. P. (2006). Residues Distant from the Active Site Influence Proteintyrosine Phosphatase 1B Inhibitor Binding. Journal of Biological Chemistry, 281(8), 5258–5266.

Kamerlin, S. C. L., Rucker, R., & Boresch, S. (2006). A targeted molecular dynamics study of WPD loop movement in PTP1B. Biochemical and Biophysical

Research Communications, 345(3), 1161–1166.

Kharchenko, S. G., Drapailo, A. B., Kalchenko, O. I., Yampolska, G. D., Shishkina, S. V., Shishkin, O. V., & Kalchenko, V. I. (2013). Thia- and Sulfonyl-

Calix[4]Arene Methylphosphonous Acids: Synthesis, Structure, and Amino Acids Binding. Phosphorus, Sulfur, and Silicon and the Related Elements,

(1-3), 243–248.

Iki, N., Kumagai, H., Morohashi, N., Ejima, K., Hasegawa, M., Miyanari, S., & Miyano, S. (1998). Selective oxidation of thiacalix[4]arenes to the sulfinyl-

and sulfonylcalix[4]arenes and their coordination ability to metal ions. Tetrahedron Letters, 39(41), 7559–7562.


Kumagai, H., Hasegawa, M., Miyanari, S., Sugawa, Y., Sato, Y., Hori, T., … Miyano, S. (1997). Facile synthesis of p-tert-butylthiacalix[4]arene by the

reaction of p-tert-butylphenol with elemental sulfur in the presence of a base. Tetrahedron Letters, 38(22), 3971–3972.


Buldenko, V., Kononets, L., Kobzar, O., Drapailo, A., Vyshnevsky, S., Kalchenko, V., & Vovk, A. (2017). The inhibitory potential of calixarenes against nucleotide pyrophosphatase/phosphodiesterase 1. Žurnal organìčnoï ta farmacevtičnoï hìmìï, 15(4(60)), 41–47.

Trott, O., & Olson, A. J. (2009). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization,

and multithreading. Journal of Computational Chemistry, 31(2), 455–461.

Tanchuk, V. Y., Tanin, V. O., & Vovk, A. I. (2012). Classification of Binding Site Conformations of Protein Tyrosine Phosphatase 1B. Chemical Biology

& Drug Design, 80(1), 121–128.

Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an advanced semantic chemical editor,

visualization, and analysis platform. Journal of Cheminformatics, 4(1), 17.

Phillips, J. C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., … Schulten, K. (2005). Scalable molecular dynamics with NAMD. Journal of

Computational Chemistry, 26(16), 1781–1802.

Zoete, V., Cuendet, M. A., Grosdidier, A., & Michielin, O. (2011). SwissParam: A fast force field generation tool for small organic molecules. Journal of Computational Chemistry, 32(11), 2359–2368.

Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38.https://doi.





How to Cite

Buldenko, V. M.; Trush, V. V.; Kobzar, O. L.; Drapailo, A. B.; Vyshnevsky, S. G.; Kalchenko, V. I.; Vovk, A. I. The Assessment of sulfonylcalix[4]arene Derivatives As Inhibitors of Protein Tyrosine Phosphatases. J. Org. Pharm. Chem. 2018, 16, 24-29.



Original Researches