title: Study of antineoplastic action of novel isomeric derivatives of 4-thiazolidinone.
abstract: 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.
authors: V V
authors: VV
authors: Chumak
authors: M R
authors: MR
authors: Fil
authors: R R
authors: RR
authors: Panchuk
authors: B S
authors: BS
authors: Zimenkovsky
authors: D Ya
authors: DY
authors: Havrylyuk
authors: R B
authors: RB
authors: Lesyk
authors: R S
authors: RS
authors: Stoika
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D053938:DNA Fragmentation; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D019169:Jurkat Cells; D061986:MCF-7 Cells; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D011720:Pyrazoles; D053778:Thiazolidines; D053181:Caspase 8; D053453:Caspase 9