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Registration Number

0224U032398, 0120U102613 , R & D reports

Title

Joint project: Synthesis and use of calixarens as modulators of biochemical processes and possible platforms for creation of new drugs. Section 1. Calixarens – promising effectors of biochemical processes.

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Синтез і використання каліксаренів як модуляторів біохімічних процесів та можливих платформ для створення нових ліків. Розділ 1. Каліксарени – перспективні ефектори біохімічних процесів

Head

Kosterin Serhii O., Доктор біологічних наук

Registration Date

04-10-2024

Organization

Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine

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The aim of this project is to create and study the properties of calix[4]arenes as promising nano-sized modulators of the energy status of cells, the energy-dependent transport of Ca ions in them, and to study the interaction of these compounds with polymerization centers located in the E-region of fibrin. The following results were obtained. Using a suspension of myometrial cells treated with digitonin solution, flow cytometry and a potential-sensitive TMRM probe, it was shown that 1 μM calix[4]arenes C-1191 and C-1192 increase the level of mitochondrial membrane polarization. It was shown that 100 μM thiacalyx[4]arene C-1087 exerts the most significant inhibitory effect on Ca2+, Mg2+-ATPase activity in the plasma membrane of myometrial cells compared to other analogues of calix[4]arene C-90, and practically does not affect specific activities of other membrane ATPases. The calculated value of the inhibition coefficient I0.5 is 9.4±0.6 µM, the value of the Hill coefficient nH is 0.58±0.03. With the help of confocal microscopy using the Ca2+sensitive fluorescent probe fluo4, it was shown that the application of thiacalyx[4]arene C-1087 to immobilized uterine myocytes leads to an increase in the intracellular Ca2+ concentration. Chalcone-containing calix[4]renes C-1012, C-1024 and C-1011 (10 μM ) inhibit energy-dependent Ca2+ accumulation and H+-Ca2+ exchanger in isolated mitochondria in a time-dependent manner. With a combination of in vitro and in silico approaches, the ability of calix[4]arene C-145 to inhibit fibrin polymerization by directly blocking the "A" center of polymerization was substantiated. It has been proven that three bisphosphonic acid residues in the calix[4]arene structure are sufficient for effective binding to fibrin, but the existence of the fourth such residue in calix[4]arene C145 increases the dissociation time of the inhibitory complex and makes it the most effective inhibitor and a potential the basis for creating antithrombotic agent.

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Babich Lidiia H.
Veklich Tetiana O.
Hrynenko Tetiana V.
Danylovych Hanna V.
Danylovuch Yurii V.
Karakhim Serhii O.
Komisarenko Serhii V.
Korolova Daria S.
Pyrohova Liudmyla V.
Platonova Tetiana M.
Volodymyr O. Chernyshenko
Chernyshenko Tamara M.
Chunikhin Oleksandr Yu.
Shlykov Serhii H.
Yusova Olena I.