Rodik R. Synthesis, structure, physico-chemical properties and bioactivity of aminocalixarene derivatives

Українська версія

Thesis for the degree of Doctor of Science (DSc)

State registration number

0524U000215

Thesis Registration Form

0524U000215.pdf

Applicant for

Roman V. Rodik

Specialization

02.00.03 - Органічна хімія

Date of defense

11-07-2024

Specialized Academic Board

Д26.217.01

Institute of Organic Chemistry NAS of Ukraine

Essay

The development of rational methods for the targeted functionalization of aminocalixarene and aminothiacalixarene three-dimensional molecular platforms with biorelevant groups, investigation of the spatial structure, physicochemical properties and evaluation of biological activity of the synthesized compounds are considered in the Doctoral thesis. The preparative synthetic methods for di-, tri- and tetra-substituted aminocalixarenes and aminothiacalixarenes with hydroxyl and alkoxyl groups on the lower rim of the macrocycle were developed as part of the dissertation project. These macrocycles were used as starting compounds for obtaining of biorelevant nitrogen-containing derivatives. The methods of synthesis involve ipso-nitration of tert-butylcalixarenes with nitric/acetic acids mixture and nitration of thiacalixarenes with nitrogen dioxide. The following step is reduction of the obtained nitro derivatives. New preparative synthetic methods were developed and a library of polyamido¬calixarenes was produced for biological investigations. Latter were synthesized in one step by acylation of aminocalixarenes with carboxylic acids in the presence of condensing agents: carbodiimides and carbonyldiimidazole. Structural analogues of paracetamol were synthesized by treatment of amino(thia)calixarenes with (trifluoro)acetic anhydrides. The methods of synthesis of calixarene bis-aryl(hetaryl)aminophosphonic acids and their monoethyl esters have been developed. They are based on the interaction of iminocalixarenes with sodium diethyl phosphite or the phosphorylating system diethyl phosphite/diisopropylethylamine/chlorotrimethylsilane and the subsequent removal of the phosphonate fragments ethyl groups with LiBr or by treatment of (CH3)3SiBr/CH3OH. (Thia)сalixarenes containing sulfonylamidine groups on the macrocycle’s upper rim and various combinations of hydroxyl and alkyl substituents on the lower rim were synthesized through the reaction of amino(thia)calixarenes with N-sulfonylimidoyl chlorides. Calixarenes, modified with N-acyl(sulfonyl)urea groups on the upper rim and hydroxyl or alkyl (C3-C16) groups on the lower rim, were obtained in one stage through the acylation of aminocalixarenes with sulfonyl(acyl)isocyanates. According to the NMR spectra, the macrocycles adopt a cone-like conformation with syn-oriented pharmacophoric groups. The methods were developed for synthesizing cone-shaped polycationic amphiphilic calixarenes, which contain functional groups (ОН, NH2, CH=O, CH2C≡CH) on the macrocycle’s upper rim, including those amenable to click reactions. They consist in the reaction of conical tetrakis-chloromethyltetraalkoxycalixarenes with substituted methyldialkylamines and N-substituted imidazoles. The self-association of amphiphilic calixarenes in aqueous solutions was investigated using a complex of physicochemical methods. It was determined that the critical micelle concentration decreases with increasing length of alkyl groups and reaches values of less than 1 µM. It was observed that, depending on the length of the lower rim alkyl groups, micelles (4-8 nm) and/or vesicles form in water solutions. Methods were developed for synthesizing fluorescent organic nanoparticles, involving click reactions of diazido-cyanines with calixarene micelles, containing acetylene groups. The synthesized nanoparticles with Cy3-groups have a diameter of 7 nm and are twice as bright as commercial cadmium-selenium nanoparticles QD-585. The results of biological evaluations of synthesized calixarenes indicate their high activity in vitro and in vivo. Thus, it was shown that stable positively charged particles with 50-65 nm size are hierarchically formed due to the interaction of calixarene micelles with DNA. These nanoparticles penetrate cells and show efficient transfection (83%) in complex with DOPE. This is much better compared to commercial agents. The synthesized fluorescent nanoparticles can penetrate membranes and selectively mark cell compartments. These nanoparticles can be used for bioimaging in cytology and vectors in theranostics. Tetracationic tetrapropoxycalixarenes have demonstrated high antibacterial properies, with MICs of 9-45 μM. In vivo investigations have established that sulfonyl(acyl)carbamidocalixarenes exhibit a hypoglycemic effect and reduce the glucose concentration in blood to 40-55% of the initial level. The relationships between structure of sulfonylamidinothiacalixarenes and calixarene aminophosphonic acids and their inhibitory effect on the Ca2+,Mg2+-ATP- and Na+,K+-ATP-dependent pumps of smooth muscle cells were studied. The tetrasulfonylamidinothiacalixarene is an effective inhibitor of Ca,Mg-ATP-ase. Dioctyloxycalixarene-diaminophosphonic acid is the best found inhibitor Na,K-ATP-ase which is 500 times more effective than the cardioglycoside Ouabain.

Official opponents

Igor Y. Dubey
Volodymyr S. Brovarets
Igor V. Komarov

Research papers

1. Mchedlov-Petrossyan N.O., Vodolazkaya N.A., Vilkova L.N., Soboleva O.Yu., Kutuzova L.V., Rodik R.V., Miroshnichenko S.I., Drapaylo A.B. The influence of cationic tetrapropoxycalix[4]arene choline on protolytic equilibria of acid-base indicators in aqueous solutions J. Mol. Liquids. 2009; 145: 197-203. https://doi.org/10.1016/j.molliq.2008.02.009

2. Rodik R.V., Boyko V.I., Kalchenko V.I. Calixarenes in bio-medical researches (review). Curr. Med. Chem. 2009; 16(13): 1630-1655. https://doi.org/10.2174/092986709788186219

3. Мчедлов-Петросян Н. О., Богданова Л. Н., Родик Р. В., Водолазкая Н. А., Кутузова Л. В., Кальченко В.И. Агрегация катионных каликсаренов в водном растворе и влияние агрегатов на кислотно-основное равновесие индикаторов Доповіді НАНУ. 2010; 3: 148-153.

4. Rodik R.V., Klymchenko A.S., Jain N., Miroshnichenko S.I., Richert L., Kalchenko V.I. Mély Y. Virus-sized DNA nanoparticles for gene delivery based on micelles of cationic calixarenes. Chem. Eur. J. 2011; 17: 5526–5538. https://doi.org/10.1002/chem.201100154

5. Cherenok S.O., Miroshnichenko S.I., Drapailo A.B., Kalchenko O.I., Rodik R.V., Boyko V.I., Matveev Y.I., Ruban A.V., Kаlchеnkо V.I. Supramolecular chemistry of Phosphorus-containing (thia)calixarenes. Phosphorus, Sulfur Silicon Relat. Elem. 2011; 186: 878-883.

6. Kalchenko O.I., Cherenok S.O., Rodik R.V., Drapailo A.B., Miroshnichenko S.I., Kаlchеnkо V.I. HPLC study of phosphorylcalixarene complexation with organic substrates. Phosphorus, Sulfur Silicon Relat. Elem. 2011; 186: 898-902. https://doi.org/10.1080/10426507.2010.522635

7. Родік Р.В. Регіоселективний синтез та хімічні перетворення 5,11-діаміно-17,23-ди-трет-бутил-25,26-дипропокси-27,28-дигідроксикаліксарену. Журн. орг. фарм. хім. 2012; 10(3): 69-74. http://dspace.nbuv.gov.ua/handle/123456789/42054

8. Vodolazkaya N.A., Mchedlov-Petrossyan N.O., Bogdanova L.N., Rodik R.V., Kalchenko V.I. The influence of aggregates of calixarenes and dendrimers on the protolytic equilibria of dyes in aqueous solution. In: From Molecules to Functional Architecture. Supramolecular Interactions. Editor: Rybachenko V.I. Donetsk. East Publisher House. 2012. 49-69.

9. Ukhatskaya E., Kurkov S.V., Hjálmarsdóttir M.A., Karginov V.A., Matthews S.E., Rodik R.V., Kalchenko V.I., Loftsson T. Cationic quaternized aminocalix[4]arenes: cytotoxicity, haemolytic and antibacterial activities. Int. J. Pharm. 2013; 458: 25-30. https://doi.org/10.1016/j.ijpharm.2013.10.028

10. Rodik R.V., Klymchenko A.S., Mely Y., Kalchenko V.I. Calixarenes and related macrocycles as gene delivery vehicles (review). J. Incl. Phenom. 2014; 80: 189-200. https://doi.org/10.1007/s10847-014-0412-8

11. Сабєров В.Ш., Марічев К.О., Короткіх М.І., Швайка О.П., Родік Р.В., Драпайло А.Б., Пехтерева Т.М., Комаровська-Порохнявець О.З., Лубенець В.І., Новіков В.П. Синтез і антимікробна активність прекарбенових та металокарбенових сполук ряду імідазолу. Журн. орг. фарм. хім. 2014; 12(2): 36-43. https://doi.org/10.24959/ophcj.14.790

12. Ukhatskaya E., Kurkov S.V., Rodik R.V., Kalchenko V.I., Matthews S.E., Jansook P., Loftsson T. Surface activity and self-aggregation ability of three cationic quaternized aminocalix[4]arenes. J. Incl. Phenom. 2014; 79: 473-483. https://doi.org/10.1007/s10847-013-0370-6

13. Cheipesh T.A., Zagorulko E.S., Mchedlov-Petrossyan N.O., Rodik R.V., Kalchenko V.I. The difference between the aggregates of short-tailed and long-tailed cationic calix[4]arene in water as detected using ﬂuorescein dyes. J. Mol. Liq. 2014; 193: 232-238. https://doi.org/10.1016/j.molliq.2013.12.049

14. Shatursky O.Y., Kasatkina L.A., Rodik R.V., Cherenok S.O., Shkrabak O.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; 12: 9811-9821. https://doi.org/10.1039/C4OB01886A

15. Rodik R.V., Anthony A.-S., Kalchenko V.I., Mély Y., Klymchenko A.S. Cationic amphiphilic calixarenes to compact DNA into small nanoparticles for gene delivery. New J. Chem. 2015; 39: 1654-1664. https://doi.org/10.1039/C4NJ01395F

16. Родік Р.В. Антимікробна та антивірусна активність каліксаренів. Журн. орг. фарм. хім. 2015; 13(1): 67-78. https://doi.org/10.24959/ophcj.15.830

17. Родік Р.В. Синтез та властивості триамінодипропокси-трет-бутилкаліксарену Укр. хім. журн. 2015; 81(3-4): 40-46. https://ucj.org.ua/index.php/journal/issue/view/85/3-2015

18. Rodik R.V., Boyko V.I., Kalchenko V.I., Calixarenes in biotechnology and bio-medical researches. Front. Med. Chem. 2016; 8: 206-301. https://doi.org/10.2174/9781681081755116080008

19. Shulov I., Rodik R.V., Arntz Y., Reisch A., Kalchenko V.I., Klymchenko A.S. Protein-sized bright fluorogenic nanoparticles based on cross-linked calixarene micelles with cyanine corona. Angew. Chem. Int. Ed. 2016; 55(51): 15884-15888. https://doi.org/10.1002/anie.201609138.

20. Rodik R., Cherenok S., Kalchenko O. Yesypenko O., Lipkowski J., Kalchenko V. Functional calixarenes for material and life science. Curr. Org. Chem. 2018; 22: 2200-2222. https://doi.org/10.2174/1385272822666181015141327

21. Chalenko N.M., Rodik R.V., Syrova G.O. Synthesis and biological activity of bis-mefenamidocalixarene J. Org. Pharm. Chem. 2019; 17(3): 21-25. https://doi.org/10.24959/175951

22. Danylovych H.V., Danylovych Yu.V., Rodik R.V., Gurska V.T., Kalchenko V.I., Kosterin S.O. Calix[4]arenes modulate Ca2+-dependent processes in smooth muscle cells mitochondria. Chemistry Research Journal. 2019; 4(6): 109-122.

23. Ostos F.J., Lebrón J.A. López-Cornejo P., López-López M., García-Calderón M., García-Calderón C.B., Rosado V.I., Kalchenko V.I., Rodik R.V., Moyá M.L. Self-aggregation in aqueous solution of amphiphilic cationic calix[4]arenes. Potential use as vectors and nanocarriers. J. Mol. Liq. 2020; 304: 112724. https://doi.org/10.1016/j.molliq.2020.112724.

24. Cheipesh T.A., Kharchenko D.V., Taranets Y.V., Rodik R.V., Mchedlov-Petrossyan N.O., Poberezhnyk M.M., Kalchenko V.I. Reaction rates in aqueous solutions of cationic colloidal surfactants and calixarenes: Acceleration and resolution of two steps of fluorescein diesters hydrolysis. Colloids Surf., A: 2020; 606: 125479. https://doi.org/10.1016/j.colsurfa.2020.125479.

25. Lebrón J.A., López-López M., García-Calderón C.B., V. Rosado I., Balestra F.R., Huertas P., Rodik R.V., Kalchenko V.I., Bernal E., Moyá M.L., López-Cornejo P., Ostos F.J. Multivalent calixarene-based liposomes as platforms for gene and drug delivery. Pharmaceutics. 2021; 13: 1250. https://doi.org/10.3390/pharmaceutics13081250.

26. Cheipesh T.A., Mchedlov–Petrossyan N.O., Bogdanova L.N., Kharchenko D.V., Roshal A.D., Vodolazkaya N.A., Taranets Yu.V., Shekhovtsov S.V., Rodik R.V., Kalchenko V.I. Aggregates of cationic calix[4]arenes in aqueous solution as media for governing protolytic equilibrium, fluorescence, and kinetics. J. Mol. Liq. 2022; 366: 119940. https://doi.org/10.1016/j.molliq.2022.119940.

27. Rucins M., Rodik R., Plotniece A., Pikun N., Plotniece M., Sobolev A., Kalchenko V., Pajuste K. Data for characterisation of nanoformulations formed by cationic 1,4-dihydopyridine and calix[4]arene compositions. Data Brief. 2022; 41: 107988. https://doi.org/10.1016/j.dib.2022.107988

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