Ukr.Biochem.J. 2022; Volume 94, Issue 4, Jul-Aug, pp. 18-35


Inhibition of plasma membrane Сa(2+),Mg(2+)-АТРase by сalixarene sulfonylamidines. Structure-activity relationship

O. A. Shkrabak1*, T. O. Veklich1, R. V. Rodik2,
V. I. Kalchenko2, S. O. Kosterin1

1Muscle Biochemistry Department, Palladin Institute of Biochemistry,
National Academy of Sciences of Ukraine, Kyiv;
2Phosphoranes Chemistry Department, Institute of Organic Chemistry,
National Academy of Sciences of Ukraine, Kyiv

Received: 07 September 2022; Revised: 26 October 2022;
Accepted: 04 November 2022; Available on-line:  14 November 2022

Previously we have already shown that tetrasulfonylamidinecalixarene C-90 inhibited plasma membrane Са2+,Mg2+-АТРаse of smooth muscle cells selectively to other ATPases of plasma membrane. To inhance the inhibitory effect of calixarenes several alkoxycalixarene sulfonylamidines structurally similar to calixa­rene C-90 were synthesized and their effects on the mentioned enzyme activity, the level of cytoplasmic Ca2+ concentration and hydrodynamic diameter of isolated smooth muscle cells were checked. It was shown that sulfonylamidino groups are crucial for Са2+,Mg2+-АТРаse inhibition, the efficiency of inhibition depends on their quantity and spatial orientation at the upper rim of calixarene macrocycle. Introduction of phenyl or tert-butyl groups into the upper rim and of long alkyl chains into the lower rim led to only slightl increase of inhibition efficiency. The inhibitory effect of studied calixarenes on Са2+,Mg2+-АТРаse correlated with effects on cytosolic Ca2+ concentration and hydrodynamic diameter of smooth muscle cells. The obtained results are important for creation of more effective and selective inhibitors of plasma membrane Са2+,Mg2+-АТРаse as regulators of smooth muscle contractility.

Keywords: , , ,


  1. Romero R, Avila C, Brecus CA, Mazor M. Uterine contractility, (Ed: R.E. Garfield). Serono Simposia, Norwell, Massachuses, 1990; 319-353.
  2. Hertelendy F, Zakar T. Regulation of myometrial smooth muscle functions. Curr Pharm Des. 2004;10(20):2499-2517. PubMed, CrossRef
  3. Floyd R, Wray S. Calcium transporters and signalling in smooth muscles. Cell Calcium. 2007;42(4-5):467-476. PubMed, CrossRef
  4. Pande J, Szewczyk MM, Kuszczak I, Grover S, Escher E, Grover AK. Functional effects of caloxin 1c2, a novel engineered selective inhibitor of plasma membrane Ca(2+)-pump isoform 4, on coronary artery. Cell Mol Med. 2008;12(3):1049-1060. PubMed, PubMedCentral, CrossRef
  5. Giuliani M, Morbioli I, Sansone F, Casnati A. Moulding calixarenes for biomacromolecule targeting. Chem Commun (Camb). 2015;51(75):14140-14159. PubMed, CrossRef
  6. Nimse SB, Kim T. Biological applications of functionalized calixarenes. Chem Soc Rev. 2013;42(1):366-386.
    PubMed, CrossRef
  7. Coleman AW, Jebors S, Cecillon S, Perret P, Garin D, Marti-Battle D, Moulin M. Toxicity and biodistribution of para-sulfonato-calix[4]arene in mice. New J Chem. 2008;32(5):780-782. CrossRef
  8. Rodik RV, Boyko VI, Kalchenko VI. Calixarenes in biotechnology and bio-medical researches. Front Med Chem. 2016;8:206-301. CrossRef
  9. Paclet MH, Rousseau CF, Yannick C, Morel F, Coleman AW. An Absence of Non-specific Immune Response towards para-Sulphonato-calix[n]arenes. J Incl Phenom Macrocycl Chem. 2006;55(3-4):353–357. CrossRef
  10. Vovk AI, Kalchenko VI, Cherenok SA, Kukhar VP, Muzychka OV, Lozynsky MO. Calix[4]arene methylenebisphosphonic acids as calf intestine alkaline phosphatase inhibitors. Org Biomol Chem. 2004;2(21):3162-3166. PubMed, CrossRef
  11. Shatursky OYa, Kasatkina LA, Rodik RV, Cherenok SO, Shkrabak AA, Veklich TO, Borisova TA, Kosterin SO, Kalchenko VI. Anion carrier formation by calix[4]arene-bis-hydroxymethylphosphonic acid in bilayer membranes. Org Biomol Chem. 2014;12(48):9811-9821. PubMed, CrossRef
  12. Veklich TA, Shkrabak AA, Slinchenko NN, Mazur II, Rodik RV, Boyko VI, Kalchenko VI, Kosterin SA. Calix[4]arene C-90 selectively inhibits Ca2+,Mg2+-ATPase of myometrium cell plasma membrane. Biochemistry (Mosc). 2014;79(5):417-424. PubMed, CrossRef
  13. Rodik RV, Boyko VI, Danylyuk OB, Suwinska K, Tsymbal IF, Slinchenko NV, Babich LG, Shlykov SO, Kosterin SO, Lipkowski J, Kalchenko VI. Calix[4]arenesulfonylamidines. Synthesis, structure and influence on Mg2+, ATP-dependent calcium pumps. Tetrahedron Lett. 2005;46(43):7459-7462. CrossRef
  14. Stoikov II, Agafonova MN, Padnya PL, Zaikov EN, Antipin IS. New membrane carrier for glutamic acid based on p-tert-butylcalix[4]arene 1,3-disubstituted at the lower rim. Mendeleev Commun. 2009;19(3):163-164. CrossRef
  15. Boyko VI, Podoprigorina AA, Yakovenko AV, Pirozhenko VV, Kalchenko VI. Alkylation of narrow rim calix[4]arenes in a DMSO-NaOH medium. J Incl Phenom. 2004;50(3):193-197. CrossRef
  16. Rassukana YV, Onys’ko PP, Grechukha AG, Sinitsa AD. N-(Arylsulfonyl)trihalogenoacetimidoyl chlorides and their reactions with phosphites. Eur J Org Chem. 2003;2003(21):4181-4186. CrossRef
  17. Iwamoto I, Araki K, Shinkai S. Syntheses of all possible conformational isomers of O-alkyl-p-t-butylcalix[4]arenes. Tetrahedron. 1991;47(25):4325-4342.
  18. Struck O, Chrisstoffels LA, Lugtenberg RJ, Verboom W, van Hummel GJ, Harkema S, Reinhoudt DN. Head-to-Head Linked Double Calix[4]arenes: Convenient Synthesis and Complexation Properties. J Org Chem. 1997;62(8):2487-2493. PubMed, CrossRef
  19. Van Wageningen AMA, Snip E, Verboom W, Reinhoudt DN, Boerrigter H. Synthesis and application of iso(thio)cyanate-functionalised calix[4]arenes. Liebigs Ann. 1997;1997(11):2235-2245. CrossRef
  20. Veklich TO, Kosterin SO. Comparative study of properties of Na+,K+-ATPase and Mg2+-ATPase of the myometrium plasma membrane. Ukr Biokhim Zhurn. 2005;77(2):66-75. (In Ukrainian). PubMed
  21. Kondratiuk TP, Bychenok SF, Prishchepa LA, Babich LG, Kurskiy MD. Isolation and characteristics of the plasma membrane fraction from the swine myometrium. Ukr Biokhim Zhurn. 1986;58(4):50-56. (In Russian). PubMed
  22. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-254. pm id=”942051″], CrossRef
  23. Mollard P, Mironneau J, Amedee T, Mironneau C. Electrophysiological characterization of single pregnant rat myometrial cells in short-term primary culture. Am J Physiol. 1986;250(Pt 1):C47-C54. PubMed, CrossRef
  24. Flynn ER, Bradley KN, Muir TC, McCarron JG. Functionally separate intracellular Ca2+ stores in smooth muscle. J Biol Chem. 2001;276(39):36411-36418. PubMed, CrossRef
  25. Valente RC, Capella LS, Monteiro RQ, Rumjanek VM, Lopes AG, Capella MAM. Mechanisms of ouabain toxicity. FASEB J. 2003;17(12):1700-1702. PubMed, CrossRef
  26. Wang H, Haas M, Liang M, Cai T, Tian J, Li S, Xie Z. Ouabain assembles signaling cascades through the caveolar Na+/K+-ATPase. J Biol Chem. 2004;279(17):17250-17259. PubMed, CrossRef
  27. Veklich TO, Kosterin SO, Shynlova OP. Cationic specificity of a Ca2+-accumulating system in smooth muscle cell mitochondria. Ukr Biokhim Zhurn. 2002;74(1):42-48. (In Ukrainian). PubMed
  28. Rathbun WB, Betlach MV. Estimation of enzymically produced orthophosphate in the presence of cysteine and adenosine triphosphate. Anal Biochem. 1969;28(1):436-445. PubMed, CrossRef
  29. Danylovych YuV, Сhunikhin AJu, Danylovych GV. [Investigation of the changes in uterine myocytes size depending on contractile activity modulators by photon correlation spectroscopy. Fiziol Zh. 2013;59(1):32-39. (In Ukrainian). PubMed
  30. Vrachnis N, Malamas FM, Sifakis S, Deligeoroglou E, Iliodromiti Z. The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents. Int J Endocrinol. 2011;2011:350546. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.