Ukr.Biochem.J. 2014; Volume 86, Issue 6, Nov-Dec, pp. 96-105


Study of antineoplastic action of novel isomeric derivatives of 4-thiazolidinone

V. V. Chumak1,2, М. R. Fil’2, R. R. Panchuk2, B. S. Zimenkovsky3,
D. Ya. Havrylyuk3, R. B. Lesyk3, R. S. Stoika1,2

1Ivan Franko Lviv National Univesity, Ukraine;
2Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv;
3Danylo Halytsky Lviv National Medical University, Ukraine;

Pyrazole- and aryl-substituted derivatives of 4-thiazolidinone belong to a perspective group of compounds with potential antitumor action. Earlier, we have demonstrated high toxicity in vitro of several 4-thiazolidinones derivatives towards tumor cell lines. To further enhance the antitumor activity of novel 4-thiazolidinones, their chemical scaffold was optimized, and new pyrazole-thiazolidinones were synthesized. That allowed us to combine in one molecule the potential pharmacophore centres of previously tested compounds. As a result, “hybrid” 4-thiazolidinones exhibit higher toxicity in vitro toward tumor cells of various origin. The molecular mechanisms of antineoplastic activity of these compounds and intensity of induction of apoptosis strongly depended on the position of the substituent in the thiazolidinone cycle. In particular, Les-3661 compound, containing pyrazoline fragment in the 4th position of thiazolidinone core, exhibits 14 times higher cytotoxic activity towards tumor cells (LC50 = 3 µM) in comparison to its 2-substituted isomer Les-3713 (LC50 = 42 µM). It is demonstrated that in terms of underlying molecular mechanisms for cytotoxic effect the Les-3661 compound induced caspase-8 and caspase-9 dependent mixed-type of apoptosis, while Les-3713 induced apoptosis mediated only by the caspase-8.

Keywords: , ,


  1. Lesyk RB, Zimenkovsky BS. 4-Thiazolidones: Centenarian history, current status and perspectives for modern and organic and medicial chemistry. Curr Org Chem. 2004;8(16):1547-77. CrossRef
  2. Zimenkovsky BS, Lesyk RB. 4-thiazolidones. Chemie, physiological action, perspectives. Vinnytsya: Nova Knyga, 2004. P. 106.
  3. Zheng W, Degterev A, Hsu E, Yuan J, Yuan C. Structure-activity relationship study of a novel necroptosis inhibitor, necrostatin-7. Bioorg Med Chem Lett. 2008 Sep 15;18(18):4932-5.  PubMed, CrossRef
  4. Lesyk RB, Zimenkovsky BS, Kaminskyy DV, Kryshchyshyn AP, Havrylyuk DYa, Atamanyuk DV, Subtel’na IYu, Khyluk DV. Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group. Biopolym Cell. 2011;27(2):107-17. CrossRef
  5. Havrylyuk D., Zimenkovsky B., Vasylenko O., Lesyk R. Synthesis, anticancer and antiviral activity of new 2-pyrazoline substituted 4-thiazolidinones. J Heterocycl Chem. 2013;50(S1):E55-62. CrossRef
  6. Havrylyuk D, Zimenkovsky B, Vasylenko O, Day CW, Smee DF, Grellier P, Lesyk R. Synthesis and biological activity evaluation of 5-pyrazoline substituted 4-thiazolidinones. Eur J Med Chem. 2013 Aug;66:228-37. PubMed, CrossRef
  7. Zimenkovsky B. S., Lesyk R. B. 4-thiazolidones and their та related heterocyclic systems. New research directions of Pharmaceutical, Organic and Bioorganic Chemistry of Danylo Halytsky Lviv National Medical Univesity. Clin Pharm Pharmacother Med Standard. 2010;(3-4):14-31.
  8. Panchuk RR, Chumak VV, Fil’ MR, Havrylyuk DYa, Zimenkovsky BS, Lesyk RB, Stoika RS. Study of molecular mechanisms of proapoptotic action of novel heterocyclic 4-thiazolidone derivatives. Biopolym Cell. 2012;28(2):121-128. CrossRef
  9. Havrylyuk D, Zimenkovsky B, Vasylenko O, Zaprutko L, Gzella A, Lesyk R. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. Eur J Med Chem. 2009 Apr;44(4):1396-404. PubMed, CrossRef
  10. Havrylyuk D, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Synthesis of new 4-thiazolidinone-, pyrazoline-, and isatin-based conjugates with promising antitumor activity. J Med Chem. 2012 Oct 25;55(20):8630-41. PubMed, CrossRef
  11. Freshney R. Culture of animal cells. Мoskow: Мyr, 1989. P. 257-276. (In Russian).
  12. Hsiao WT, Tsai MD, Jow GM, Tien LT, Lee YJ. Involvement of Smac, p53, and caspase pathways in induction of apoptosis by gossypol in human retinoblastoma cells. Mol Vis. 2012;18:2033-42. Epub 2012 Jul 20. PubMed, PubMedCentral
  13. Jayadev S. Flow Cytometric Analysis of Cell Cycle. Exp. Cell Res. 1994;(207):142-151.
  14. Janus P., Pakuіa-Cis M., Kalinowska-Herok M., Kashchak N., Szoіtysek K., Pigіowski W., Widlak W., Kimmel M., Widlak P. NF-kB signaling pathway is inhibited by heat shock independently of active transcription factor HSF1 and increased levels of inducible heat shock proteins. Genes Cells. 2011 Dec;16(12):1168-75.  PubMed, CrossRef
  15. Darbre A. Practical protein chemistry. Мoskow: Мyr, 1989. P. 295-296. (In Russian).
  16. Havrylyuk D, Zimenkovsky B, Vasylenko O, Zaprutko L, Gzella A, Lesyk R. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. Eur J Med Chem. 2009 Apr;44(4):1396-404. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.