COMPARATIVE STUDY OF THE CYTOTOXIC PROPERTIES OF ISATIN-CONTAINING DERIVATIVES OF 4-THIAZOLIDINONE WITH DIFFERENT STRUCTURE TOWARD HUMAN TUMOR CELLS IN VITRO

V. V. Chumak, R. R. Panchuk, N. O. Manko, D. Ya. Havrylyuk, R. V. Lesyk, L. I. Kobylinska, B. S. Zimenkovsky, R. S. Stoika


DOI: http://dx.doi.org/10.30970/sbi.0802.357

Abstract


Compounds on the basis of 4-thiazolidinone and its isatin-containing derivatives are characterized by a broad spectrum of biological activities and are potential antineoplastic agents. We have shown that the combination of 4-thiazolidinone and isatine (1H-indole-2,3-dione) in one molecule enhances the cytotoxic action of novel compounds towards lukemic and carcinoma cells in vitro. The level of cytotoxic action of ID-3833, ID-4522, ID-4523, ID-4524, ID-4525, ID-4526, ID-4527 compounds strongly depends on the presence of a halogen in the 5th position of the indoline moiety and the type of the atom (chlorine or bromine) in the aryl groups in the 3rd and 5th positions in pyrazoline moiety. Compound ID-3833 demonstrates the highest activity, which can be associated with the presence of bromine in the 5th position of indoline and 4-methoxyphenyl in the 5th position of pyrazoline and naphthyl in the 3rd position of pyrazoline. ID-4524 compound, whose molecule contains 5-bromindoline and two para-chlorophenyl groups also possessed high cytotoxic effect towards tumor cells. At the same time, ID-4522 compound was found to possess the lowest cytotoxic activity towards tumor cells. Like ID-4524 compound, it is characterized by the presence of two para-chlorophenyl groups in 3rd and 5th position of pyrazoline in isatin-pyrazoline-thiazolidinonr system, but it does not contain halogen in the 5th position of the indoline moiety. Thus, cytotoxic effect of isatin-containing 4-thiazolidinones mostly depends on the presence of halogen in the 5th position of the indoline, and the type of halogen in the 3rd and 5th position of the aryl groups of pirazoline cycle. All of these substances induce apoptosis in tumor cells. It has been shown that the ID-3833 substance induces apoptosis of mixed type, which includes the ER stress and mitochondrial apoptosis. The identified structure-functional relationships of 4-thiazolidones will be of high importance for further enhancement of their antineoplastic activity towards tumor cells.


Keywords


4-thiazolidinone, isatin, leukemia cells, carcinoma cells

References


1. Zimenkovsky B.S., Lesyk R.B. 4-thiazolidones. Chemie, physiological action, perspectives. Vinnytsya: Nova Knyga, 2004. - P. 106. (In Ukrainian)

2. Esmaeelian B., Abbott C. A., Le Leu, R. K., Benkendorff K. 6-Bromoisatin Found in Muricid Mollusc Extracts Inhibits Colon Cancer Cell Proliferation and Induces Apoptosis, Preventing Early Stage Tumor Formation in a Colorectal Cancer Rodent Model. Mar. Drugs, 2014; 12: 17-35.
https://doi.org/10.3390/md12010017
PMid:24368567 PMCid:PMC3917258

3. Havrylyuk D., Zimenkovsky B., Vasylenko O. et al. Synthesis of new 4-thiazolidinone-, pyrazoline-, and isatin-based conjugates with promising antitumor activity. Journal of Medicinal Chemistry, 2012; 55: 8630-8641.
https://doi.org/10.1021/jm300789g
PMid:22992049

4. Kaminskyy D., Khulyk D., Vasylenko O. et al. A Facile Synthesis and Anticancer Activity Evaluation of Spiro[Thiazolidinone-Isatin] Conjugates. Scientific Pharmacology, 2011; 79: 763-777.
https://doi.org/10.3797/scipharm.1109-14
PMid:22145104 PMCid:PMC3221502

5. Havrylyuk D., Zimenkovsky B., Vasylenko O. et al. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. European Journal of Medicinal Chemistry, 2009; 44: 1396-1404.
https://doi.org/10.1016/j.ejmech.2008.09.032
PMid:19000643

6. Krishnegowda G., Prakasha Gowda A.S., Tagaram H.R.S. et al. Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway. Bioorg. Med. Chem, 2011; 19(20): 6006-6014.
https://doi.org/10.1016/j.bmc.2011.08.044
PMid:21920762 PMCid:PMC3235409

7. Sachdeva H., Saroj R., Dwivedi D. Nano-ZnO Catalyzed Multicomponent One-Pot Synthesis of Novel Spiro (indoline-pyranodioxine) Derivatives. The Scientific World Journal, 2014; 2014: 1-10.
https://doi.org/10.1155/2014/427195
PMid:24683341 PMCid:PMC3933407

8. Kara L., Vine Julie M., Locke Marie Ranson et al. In vitro cytotoxicity evaluation of some substituted isatin derivatives. Bioorganic & Medicinal Chemistry, 2007; 15(2): 931-938.
https://doi.org/10.1016/j.bmc.2006.10.035
PMid:17088067

9. Peterson G.L. А simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal. Biochemistry, 1977; 83(2): 346-358.
https://doi.org/10.1016/0003-2697(77)90043-4

10. Gudipati R., Anreddy R.N.R., Manda S. Synthesis, characterization and anticancer activity of certain 3-{4-(5-mercapto-1,3,4-oxadiazole-2-yl)phenylimino}indolin-2-one derivatives. Saudi Pharmaceutical Journal, 2011; 19: 153-158.
https://doi.org/10.1016/j.jsps.2011.03.002
PMid:23960753 PMCid:PMC3744961

11. Panchuk R.R., Chumak V.V., Fil' M.R. et al. Study of molecular mechanisms of proapoptotic action of novel heterocyclic 4-thiazolidone derivatives. Biopolymers and Cell; 2012; 28(2): 121-128.
https://doi.org/10.7124/bc.00003D

12. Mokhtari S., Mosaddegh M., Moghadam M.H. et al. Synthesis and cytotoxic evaluation of novel 3-substituted derivatives of 2-indolinone. Iranian Journal of Pharmaceutical Research, 2012; 11(2): 411-421.


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