Cherenok S. Calixarenephosphonic acids. Synthesis, structure and properties.

Українська версія

Thesis for the degree of Doctor of Science (DSc)

State registration number

0524U000098

Thesis Registration Form

0524U000098.pdf

Applicant for

Serhii O. Cherenok

Specialization

02.00.03 - Органічна хімія

Date of defense

26-04-2024

Specialized Academic Board

Д 26.217.01

Institute of Organic Chemistry NAS of Ukraine

Essay

The dissertation focuses on the development of preparative methods of functionalization of the upper rim of calix[4]arenes and thiacalix[4]arenes with fragments of hydroxymethylphosphonic, methylenebisphosphonic, α-ketophosphonic and hydroxymethylene-bisphosphonic acids, study of the structure, complex-formation properties and biological activity of the obtained compounds. A preparative methods for the synthesis of formylcalixarenes – building blocks for phosphorylation – have been developed. They have a different number and position of reactive aldehyde groups on the upper rim of the macrocycle, and a different number, position and length of alkyl groups on the lower rim. Reactions of monoformyl and diformylcalixarenes with trialkylphosphites in the presence of anhydrous hydrogen chloride, sodium salts of dialkylphosphites, and silyl esters of trivalent phosphorus acids afforded alkyl and silyl esters of the corresponding di-, tri-, and tetrapropoxycalixarene-hydroxymethylphosphonic acids with preparative yields. The degree of alkylation of the lower rim of diformylcalixarenes was found to affect significantly the stereochemical result of phosphorylation reactions. Respective calixarene-hydroxymethylphosphonic acids were synthesized from of the obtained esters. Alkyl esters of (thia)calixarene-methylenebisphosphonic acids were synthesized by reaction of tetrahydroxyformyl(thia)calixarenes and dialxoxyformyl-(thia)calixarenes with large excesses of sodium salts of dialkylphosphites. It was established that the reaction proceeds through the stages of formation of calixarene-hydroxymethylphosphonates and phosphorylated quinonemethides. (Thia)calixarenes containing one, two, and four fragments of methylenebisphosphonic acids on the upper rim of the macrocycle were obtained via treatment of the obtained compounds with bromotrimethylsilane and methanol. Esters of calixarene-α-ketophosphonic acids were obtained by reaction of chloride anhydrides of di- and tetra-alkylcalixarene carboxylic acids with trialkylphosphites. Their structure in solutions and in the crystalline state was determined. Calixarene-α-ketophosphonic acids were synthesized by sequential treatment of the calixarene ketophosphonates with bromotrimethylsilane and methanol. A preparative one-pot method for introducing fragments of hydroxymethylene¬bisphosphonic acids to the upper rim of calixarenes has been developed. It is based on the sequential treatment of calixarene acyl chlorides with tris(trimethylsilyl) phosphite and wet methanol. Preparative methods of regioselective alkylation of alkyl esters of tetrahydroxy¬calixarene-phosphonic acids with alcohols under the Mitsunobu reaction conditions were developed. As a result, bifunctional calixarenes with receptor groups of phosphonic acids on the upper rim, capable of binding amino acids, and 3 (methylthio)propoxy groups on the lower rim, capable of adhesion on the gold surface of microchips of conductometric sensors were obtained. Preparative methods of introducing electron-deficient pentafluorophenyl and para-tert-butyltetrafluorophenyl fragments onto the upper rim of the cone-shaped tetrapropoxycalixarene have been developed. These fragments are capable of forming sandwich complexes with anions and electron-rich aromatic molecules. Polyfluoroaryl derivatives of calixarene-diphosphonic acid and calixarene-bishydroxymethylphosphonic acid were further obtained. Stability constants of complexes of bis((3-methylthio)propoxy)calixarene-methylenebisphosphonic acid with seventeen amino acids of different nature in aqueous solution were determined by using HPLC. A conductometric sensor for the determination of arginine in aqueous solutions was created by applying the synthesized acid to the gold surface of a microchip. Using the HPLC method, it was found that calixarene-tetrakis-methylene¬bisphosphonic acid effectively binds the tetrapeptide Gly-Pro-Arg-Pro, which is involved in the process of fibrin polymerization. It was shown that calixarene and thiacalixarene-tetrakis-methylenebisphosphonic acids are effective inhibitors of fibrin polymerization and can be used as basic structures for the development of a new class of antithrombotic agents. Medical and biological studies of synthesized calixarene-phosphonic acids proved their low toxicity and diverse biological activity: calixarene-methylenebisphosphonic acid and calixarene-di-hydroxymethylphosphonic acid are potent and selective inhibitors of the Na+,K+-ATPase pump of smooth muscle cells; calixarene-α-ketophosphonic, calixarene-methylenebisphosphonic and calixarene-hydroxymethylphosphonic acids are effective inhibitors of protein tyrosine phosphatases and glutathione S-transferases. Мicelles of amphiphilic calixarene-hydroxymethylenebisphosphonic acids form supramolecular complexes with fluorescent-labeled polylysine and HIV-1 nucleocapsid and transport them throught biological membranes.

Official opponents

Valentin A. Chebanov
Volodymyr S. Brovarets
Vasyl G. Pivovarenko

Research papers

1. Vovk A., Kalchenko V., Muzychka O., Tanchuk V., Muravyova I., Shivanyuk A., Cherenok S. Kukhar V. Calixarene Methylenebisphosphonic Acids: Alkaline Phosphatase Inhibition and Docking Studies. Phosphorus, Sulfur Silicon Relat. Elem. – 2008. – V. 183 (2-3). – P. 625-626; DOI: 10.1080/10426500701793311

2. Cherenok S., Kalchenko V. Phosphorus-containing calixarenes (review). Top. Heterocycl. Chem. – 2009. – Vol. 20. – P. 229-273; DOI: 10.1007/7081_2008_12;

3. Атамась Л.І., Бойко В.І., Драпайло А.Б., Єсипенко О.А., Кальченко О.І., Клячина М.А., Матвєєв Ю.І., Мірошниченко С.І., Родік Р.В., Черенок С.О., Кальченко В.І. Cупрамолекулярна хімія каліксаренів (огляд). Журнал Органічної та Фармацевтичної Хімії. – 2009. – Т. 7 (2). – С. 28-36.

4. Kalchenko O.I., Cherenok S.О., Solovyov A.V., Kalchenko V.I. Influence of Calixarenes on Chromatographic Separation of Benzene or Uracil Derivatives. Chromatographia. – 2009. – Vol. 70 (5-6). – P. 717-721; DOI: 10.1365/s10337-009-1229-2;

5. Vovk A.I., Kononets L.A., Tanchuk V.Yu., Cherenok S.O., Drapailo A.B., Kalchenko V.I., Kukhar V.P. Inhibition of Yersinia protein tyrosine phosphatase by phosphonate derivatives of calixarenes. Bioorg. Med. Chem. Lett. – 2010. – Vol. 20. – P. 483–487; DOI: 10.1016/j.bmcl.2009.11.126;

6. Solovyov A.V., Cherenok S.O., Kalchenko O.I., Atamas L.I., Kazantseva Z.I., Koshets I.A., Tsymbal I.F., Kalchenko V.I. Synthesis and complexation of amphiphilic calix[4]arene phosphonates with organic molecules in solutions and Langmuir-Blodgett films. J. Mol. Liq. – 2011. – V. 159 (2). – P. 117-123; DOI: 10.1016/j.bmcl.2009.11.126;

7. Cherenok S.O., Yuschenko O.A., Gritsenko P.G., Lugovskoy E.V., Koshel T.A., Chernishov V.I., Koliesnik I.O., Kalchenko O.I., Komisarenko S.V., Kalchenko V.I. Synthesis of calixarenemethylenebisphosphonic acids and their influence on fibrin polymerization. Phosphorus, Sulfur Silicon Relat. Elem. – 2011. – V. 186, No. 4. – P. 964-965; DOI: 10.1080/10426507.2010.521212;

8. Lugovskoy E.V., Gritsenko P.G., Koshel T.A., Koliesnik I.O., Cherenok S.O., Kalchenko O.I., Kalchenko V.I., Komisarenko S.V. Calix[4]arene methylenebisphosphonic acids as inhibitors of fibrin polymerization. FEBS J. – 2011. – V. 278. – P. 1244 – 1251; DOI: 10.1111/j.1742-4658.2011.08045.x.

9. Cherenok S.O., Yushchenko O.A., Tanchuk V.Yu., Mischenko I.M., Samus N.V., Ruban O.V., Matvieiev Yu.I., Karpenko Yu.A., Kukhar V.P., Vovk A.I., Kalchenko V.I. Calix[4]arene-α-hydroxyphosphonic acids. Synthesis, stereochemistry and inhibition of glutathione S-transferase. Arkivoc. – 2012. – V. 4. – P. 278-298; DOI: 10.3998/ark.5550190.0013.421;

10. Kalchenko O., Cherenok S., Yushchenko O., Kalchenko V. Complexation of calix[4]arenehydroxymethylphosphonic acids with amino acіds. Binding constants determination of the complexes by HPLC method. J. Inclusion Phenom. Macrocyclic Chem. – 2013. – V. 76 (2). – P. 29-36; DOI: 10.1007/s10847-012-0169-x;

11. Kalchenko V.I., Cherenok S.O., Kosterin S.O., Lugovskoy E.V., Komisarenko S.V., Vovk A.I., Tanchuk N.Y., Kononets L.A., Kukhar V.P. Calixarene Phosphonous Acids; Synthesis and Biological Activity. Phosphorus, Sulfur Silicon Relat. Elem. – 2013. – V.188 (1-3). – P. 232-237; DOI: 10.1080/10426507.2012.743147;

12. Ruban A.V., Rozhenko A.B., Pirozhenko V.V., Shishkina S.V., Shishkin O.V., Cherenok S.O., Kalchenko V.I. Perfluorophenylcalix[4]arenes: perspective hosts for nucleophilic guests. Synthesis, structure and quantum chemical calculations. Tetrahedron Lett. – 2013. – V. 54 (27). – P. 3496-3499; DOI: 10.1016/j.tetlet.2013.04.083;

13. Trush V.V., Cherenok S.O., Tanchuk V.Yu., Kukhar V.P., Kalchenko V.I., Vovk A.I. Calix[4]arene methylenebisphosphonic acids as inhibitors of protein tyrosine phosphatase 1B. Bioorg. Med. Chem. Lett. – 2013. – V. 23 (20). – P. 5619-5623; DOI: 10.1016/j.bmcl.2013.08.040;

14. Kalchenko O.I., Cherenok S.О., Kalchenko V.I., Solovyov A.V., Gorbatchuk V.V. The study of the complexation of 5,17-bis-(N-tolyliminomethyl)-25,27-dipropoxy-calix[4]arene with benzoic acids by RP HPLC and molecular modeling methods. Журнал Органічної та Фармацевтичної Хімії. – 2013. – Т. 11 (3). – С. 3-8; DOI: 10.24959/ophcj.13.752;

15. Shatursky O.Ya, Kasatkina L.A., Rodik R.V., Cherenok S.O., Shkrabak A.A., Veklich T.O., Borisova T.A., Kosterin S.O., Kalchenko V.I. Anion carrier formation by calix[4]arene-bis-hydroxymethylphosphonic acid in bilayer membranes. Org. Biomol. Chem. – 2014. – V. 12(48). – P. 9811-9821; DOI: 10.1039/c4ob01886a;

16. Trush V.V., Tanchuk V.Y., Cherenok S.O., Kalchenko V.I., Vovk A.I. Calix[4]arene α-hydroxymethylphosphonic acids as potential inhibitors of protein tyrosine phosphatases. Журнал Органічної та Фармацевтичної Хімії. – 2014. – Т. 12 (1). – С. 39-42; DOI: 10.24959/ophcj.14.782;

17. Komisarenko S.V., Kosterin S.O., Lugovskoy E.V., Cherenok S.O., Tanchuk V.Yu., Vovk A.I., Kalchenko V.I. Synthesis and characterization of calixarene methylene bisphosphonic acids as effectors of biochemical processes. In Book: “LIGANDS: SYNTHESIS, CHARACTERIZATION AND ROLE IN BIOTECHNOLOGY”. – New York: Nova Science Publishers, Inc., 2014. – 295 p. – Chapter 3. – P. 67-116.

18. Комисаренко С.В., Кальченко В.И., Костерин С.А., Луговской Э.В., Лабинцева Р.Д., Черенок С.О., Бевза А.В. Каликс[4]аренметилен¬бисфосфоновые кислоты – перспективные наноэффекторы биохимических процессов. В книге «Наноразмерные системы и наноматериалы: исследования в Украине» /Редкол.: А.Г.Наумовец (глав. ред.); НАН Украины. – Киев: Академпериодика, 2014. – 768 с. – Глава 5 «Нанобиотехнологии». – P. 455-473.

19. Kalchenko O., Cherenok S., Rodik R., Mely Y., Kalchenko V. Complexation of calixarene hydroxymethylphosphonic acid with tryptophan and N-acetyltryptophan amide. Журнал Органічної та Фармацевтичної Хімії. – 2014. – Т. 12 (2). – С. 21-26; DOI:10.24959/ophcj.14.796;

20. Kalchenko O.I., Cherenok S.O., Savonik L.M., Solovyov A.V., Gorbatchuk V.V., Kalchenko V.I. Investigation of the sorption of calix[4]arene and calix[4]resorcinarene tetraalkylderivatives with the LiChrosorb RP 18 surface by RP HPLC and computer modeling methods. Журнал Органічної та Фармацевтичної Хімії. – 2014. – Т. 12 (3) – P. 17-22; DOI:10.24959/ophcj.14.799;

21. Kalchenko O., Cherenok S., Kalchenko V. Complexation of Calix[4]arene bis-Hydroxymethylenediphosphonic Acid with Amino acids. Binding Constants Determination by RP HPLC Method. Fr.-Ukr. J. Chem. – 2015. – V. 3(2). – P. 93-100; DOI: 10.17721/fujcV3I2P93-100; (фахове видання).

22. Kalchenko, O.; Cherenok, S.; Drapailo, A.; Kharchenko, S.; Kalchenko, V. Complexation of (thia)calix[4]arene phosphonic acids with amino acids and peptydes. Binding constants determination of the complexes by RP HPLC method. In book: Modern Directions in Chemistry, Biology, Pharmacy and Biotechnology / editor in chief Volodymyr Novikov. – Lviv: Lviv Polytechnic Publishing House, 2015, 256 p. – Р. 20-31

23. Trush V.V., Cherenok S.O., Tanchuk V.Yu., Kalchenko V.I., Vovk A.I. Evaluation of inhibition of protein tyrosine phosphatase 1B by calixarene-based α-ketophosphonic acids. Chem. Biol. Lett. – 2015. – Vol. 2 (1). – P. 1-5; DOI: http://www.pubs.iscience.in/journal/index.php/cbl/article/view/253;

24. Kalchenko O.I., Cherenok S.O., Solovyov A.V., Gorbatchuk V.V., Suikov S.Yu., Kalchenko V.I. The Study of the Complexation of Calix[4]arene and Calix[4]resorcinarene with Resin Acids by RP HPLC Method. Binding Constants Determination. Журнал Органічної та Фармацевтичної Хімії. – 2016. – Т. 14 (2). – P. 41-46; DOI: 10.24959/ophcj.16.884;

25. Kalchenko O.I., Cherenok S.O., Solovyov A.V., Suikov S.Yu., Kalchenko V.I. The study of calixarenes complexation with phenols by RP HPLC. Журнал Органічної та Фармацевтичної Хімії. – 2017. – Т. 15 (1). – С. 45-51; DOI: 10.24959/ophcj.17.910;

26. Kalchenko O., Cherenok S., Suikov S., Kalchenko V. Study of Calixarene Complexation with Biologically Active Carboxylic Acids by RP HPLC Method. Fr.-Ukr. J. Chem. – 2017. – V. 05 (2). – P. 49-55; DOI: 10.17721/fujcV5I2P49-55;

27. Rodik R, Cherenok S., Kalchenko O., Yesypenko O., Lipkowski J., Kalchenko V. Functional Сalixarenes for Material and Life Science. Curr. Org. Chem. – 2018. – Vol. 22. – P. 2196-2218;

28. Soldatkin O., Marchenko S., Soldatkina O. Cherenok S., Kalchenko O., Prynova O., Sіlenko O., Kalchenko V., Dzyadevych S. Conductometric sensor with calixarene based chemosensitive element for the arginine detection. Chem. Pap. – 2018. – V. 72 (11). – P. 2687–2697; DOI: 10.1007/s11696-018-0515-6;

29. Cherenok S., Soldatkin O., Marchenko S., Soldatkina O., Kalchenko O., Prynova O., Silenko O., Dzyadevych S., Kalchenko V. 3-Methylsulfidopropoxycalixarene methylenebisphosphonic acid for aminoacids chemosensor. Phosphorus, Sulfur Silicon Relat. Elem. – 2019. – V.194 (4-6). – P. 382-383; DOI: 10.1080/10426507.2018.1550491;

30. Кальченко., В.І.; Єсипенко, О.А.; Кальченко, О.І.; Черенок, С.О.; Бойко. В.І. Хіральні каліксарени. В книзі: Стратегія синтезу і біоактивність органічних молекул. Київ: Інтерсервіс, 2019. – С. 143-196.

31. Selihova A., Cherenok S., Kalchenko O., Kalchenko V. Tetrahydroxycalixarene methylenebisphosphonic acids: synthesis, stereochemistry, and aminoacids complexations. Phosphorus, Sulfur Silicon Relat. Elem. – 2022. – V.197 (5-6). – P.526–5528; DOI: 10.1080/10426507.2021.2011875;

32. Kalchenko O., Cherenok S., Silenko O., Kalchenko V. Influence of the nature of amino acids on the formation of supramolecular complexes with calixarene-methylene(bis)phosphonic acid. Theoretical and Experimental Chemistry. – 2022. – V.58 (4).–P.254-260; DOI: 10.1007/s11237-022-09742-5;

33. Kobzar O., Shulha Y., Buldenko V., Cherenok S., Silenko O., Kalchenko V., Vovk A. Inhibition of glutathione S-transferases by photoactive calix[4]arene α-ketophosphonic acids. Bioorg. Med. Chem. Lett. – 2022. – V.77. – P.1-7; DOI: 10.1016/j.bmcl.2022.129019;

34. Rodik R.V., Cherenok S.O., Postupalenko V.Y., Oncul S., Brusianska V., Borysko P., Kalchenko V.I., Mely Y., Klymchenko A.S. Anionic Amphiphilic Calixarenes for Peptide Assembly and Delivery. J. Colloid Interface Sci. – 2022. -V. 624. - P. 270-278; DOI: 10.1016/j.jcis.2022.05.124;

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