Ivasechko I. Antineoplastic action of new thiazole and thiazolidinone derivatives and their water-soluble forms

Українська версія

Thesis for the degree of Doctor of Philosophy (PhD)

State registration number

0823U100839

Applicant for

Specialization

  • 091 - Біологія та біохімія

25-09-2023

Specialized Academic Board

ДФ 35.246.004 (2066)

Institute of Cell Biology of the National Academy of Sciences of Ukraine

Essay

Ivasechko I. I. Antineoplastic action of new thiazole and thiazolidinone derivatives and their water-soluble forms. – Qualifying scientific work on the rights of the manuscript. Dissertation for the Doctor of Philosophy degree in specialty 091 – Biology. - Institute of Cell Biology of the National Academy of Sciences of Ukraine, Lviv, 2023. The dissertation highlights the mechanisms of potential cytotoxic action on tumor, normal and pseudo-normal mammalian cells of 28 new compounds, derivatives of pyridine-thiazoles and thiopyrano-thiazoles with a naphthoquinone fragment, as well as possibility of further application of most active forms in order to create an effective molecules with antitumor activity. Compounds were synthesized in Lviv National Medical University by research team led by Roman Lesyk, PhD, DSc, Professor. Among the newly synthesized compounds of pyridine-thiazole derivatives, inhibitors of poly (ADP-ribose) polymerases (PARP), involved in DNA repair processes, were found. The investigated compounds interact with the target by a different, from previously known PARP inhibitors, mechanism. The compound Les-6485 binds the lateral active site of PARP1 through intense hydrogen bonds and various types of Pi interactions. In addition, the molecule forms weak carbon–hydrogen bonds with Ser864 and does not occupy the benzamide binding pocket of PARP (Gly863 and Ser904 in PARP1) and (Gly429 and Ser470 in PARP2). Compounds that act as inhibitors of proteins involved in DNA repair processes play an important role in the development of the concept of synthetic lethality (a situation where two or more genes simultaneously lose their function, causing cell death) as an approach to cancer therapy. Іnvestigated compounds interact with the target by a different, from previously known PARP inhibitors, mechanism. Compounds interact with the single-stranded DNA molecule, are capable of fluorescence, and accumulate in the cell around the nucleus. As PARP inhibitors are important in the development of the concept of synthetic lethality, MGMT and BRCA1 inhibitors were used in our study to block compensatory mechanisms of DNA repair and study the potential chemical synthetic lethality of the Les-6485 and Les-5303 and these inhibitors. It is important to note that Les-6485 shows a synergistic effect in combination with an MGMT inhibitor. Studies of toxicity in vivo confirmed that it does not have a toxic effect on the body of mice of the C57BL/6 line. The study of the mechanisms of action of the thiopyrano-thiazoles with a naphthoquinone fragment showed their ability to interact with DNA electrostatically and/or by the type of intercalation. It can be noted that, in general, these compounds did not show a selective effect against tumor lines. Only HCT-116 p53-/- cells were, on average, 2 times more resistant to compounds 1, 4, and 10 compared to wild-type HCT-116wt cells. The effect of thiopyrano-thiazoles on tumor cells was similar to the effect of doxorubicin, however, their cytotoxic effect on normal and pseudo-normal cell lines was significantly lower. Study of the toxicity of the most active derivative 10 in vivo at a dose of 20 mg/kg did not cause a toxic effect on the body of mice of the C57BL/6 line. The data of experimental studies is significant for understanding the mechanisms of the effect of thiazoles on normal and tumor cells of mammals, and show possibilities of their further application in order to create effective molecules with antitumor activity.

Research papers

1. Lozynskyi, A., Zimenkovskyi, B., Ivasechko, I., Senkiv, J., Gzella, A., Karpenko, O., ... & Lesyk, R. (2019). Synthesis and cytotoxicity of new 2-oxo-7-phenyl-2, 3-dihydrothiazolo [4, 5-b] pyridine-5-carboxylic acid amides. Phosphorus, Sulfur, and Silicon and the Related Elements, 194(12), 1149-1157. https://doi.org/10.1080/10426507.2019.1633318 IF=1,046, Q4.

2. Ivasechko, I., Yushyn, I., Roszczenko, P., Senkiv, J., Finiuk, N., Lesyk, D., Holota, S., Czarnomysy, R., Klyuchivska, O., Khyluk, D., Kashchak, N., Gzella, A., Bielawski, K., Bielawska, A., Stoika, R., & Lesyk, R. (2022). Development of Novel Pyridine-Thiazole Hybrid Molecules as Potential Anticancer Agents. Molecules, 27(19), 6219. https://doi.org/10.3390/molecules27196219 IF= 4,927, Q2.

3. Lozynskyi, A., Senkiv, J., Ivasechko, I., Finiuk, N., Klyuchivska, O., Kashchak, N., ... & Lesyk, R. (2022). 1, 4-Naphthoquinone Motif in the Synthesis of New Thiopyrano [2, 3-d] thiazoles as Potential Biologically Active Compounds. Molecules, 27(21), 7575. https://doi.org/10.3390/molecules27217575 IF= 4,927, Q2.

4. Ivasechko, I., Lozynskyi, A., Senkiv, J., Roszczenko, P., Kozak, Y., Finiuk, N., Klyuchivska, O., Kashchak, N., Manko, N., Maslyak, Z., Lesyk, D., Karkhut, A., Polovkovych, S., Czarnomysy, R., Szewczyk, O., Kozytskiy, A., Karpenko, O., Khyluk, D., Gzella, A., Bielawski, K., Stoika, R., Lesyk, R. (2023). Molecular design, synthesis and anticancer activity of new thiopyrano[2,3-d]thiazoles based on 5-hydroxy-1,4-naphthoquinone (juglone). European journal of medicinal chemistry, 252, 115304. https://doi.org/10.1016/j.ejmech.2023.115304 . IF= 7,088, Q1.

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