New 4-thiazolidinone-based molecules Les-2769 and Les-3266 as possible PPARγ modulators.

Development of cancer drug-resistance is still an ongoing problem in the modern anticancer treatment. Therefore, there is a need to search for a new active substance, which may become a potential anticancer agent. 4-Thiazolidinones are well-described substances with cytotoxicity against cancer cells in vitro. Therefore, the aim of this study was to evaluate the effect of two 4-thiazolidinone-based derivatives (Les-2769 and Les-3266) on the PPARγ-dependent cytotoxicity in normal human skin fibroblasts (BJ) and squamous cell carcinoma (SCC-15) in vitro. The data obtained showed a cytotoxic effect of Les-2769 and Les-3266 used in micromolar concentrations on SCC-15 and BJ cells, manifesting by a decrease in the metabolic activity, an increase in the release of lactate dehydrogenase, and caspase-3 activity. The co-treatment of the cells with Les-3266 and an antagonist (GW9662) or an agonist (rosiglitazone) of the PPARγ receptor induced changes in the above-mentioned parameters in the BJ and SCC-15 cells, compared to the Les-3266 alone exposure; this was not found in the Les-2769-treated cells. The further analysis of the compounds indicated changes in the expression of the PPARγ, KI67, and NF-κB genes. Moreover, the tested compounds caused an increase in the level of PPARγ mRNA expression in a similar way to rosiglitazone in SCC-15, which may indicate the affinity of the compounds for PPARγ. Molecular docking is consistent with experimental in vitro data about the potential agonistic activity of Les-2769 and Les-3266 towards PPARγ receptors. Summarizing, the anticancer effect of both compounds was observed in the SCC-15 cells in vitro; moreover, the mechanism of action of Les-3266 in cells is mediated probably by interaction with the PPARγ receptor pathway, which needs in-depth study.

Development of Novel Pyridine-Thiazole Hybrid Molecules as Potential Anticancer Agents.

Novel pyridine-thiazole hybrid molecules were synthesized and subjected to physico-chemical characterization and screening of their cytotoxic action towards a panel of cell lines derived from different types of tumors (carcinomas of colon, breast, and lung, glioblastoma and leukemia), and normal human keratinocytes, for comparison. High antiproliferative activity of the 3-(2-fluorophenyl)-1-[4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl]-propenone 3 and 4-(2-{1-(2-fluorophenyl)-3-[4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl]-3-oxopropylsulfanyl}-acetylamino)-benzoic acid ethyl ester 4 was revealed. The IC50 of the compound 3 in HL-60 cells of the acute human promyelocytic leukemia was 0.57 µM, while in the pseudo-normal human cell lines, the IC50 of this compound was >50 µM, which suggests that the compounds 3 and 4 might be perspective anticancer agents. The detected selectivity of the derivatives 3 and 4 for cancer cell lines inspired us to study the mechanisms of their cytotoxic action. It was shown that preincubation of tumor cells with Fluzaparib (inhibitor of PARP1) reduced the cytotoxic activity of the derivatives 3 and 4 by more than twice. The ability of these compounds to affect DNA nativity and cause changes in nucleus morphology allows for the suggestion that the mechanism of action of the novel pyridine-thiazole derivatives might be related to inducing the genetic instability in tumor cells.

Molecular design, synthesis and anticancer activity of new thiopyrano[2,3-d]thiazoles based on 5-hydroxy-1,4-naphthoquinone (juglone).

A series of 11-substituted 9-hydroxy-3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]thiazole-2,5,10-triones 3.1-3.13 were synthesized via hetero-Diels-Alder reaction of 5-ene-4-thioxo-2-thiazolidinones and 5-hydroxy-1,4-naphthoquinone (juglone). The structure of newly synthesized compounds was established by means of spectral data and a single-crystal X-ray diffraction analysis. The synthesized compounds were tested on a panel of cell lines representing different types of cancer as well as normal and pseudonormal cells and peripheral human blood lymphocytes. Compound 3.10 was found to be the most active derivative, exhibiting a cytotoxic effect similar to doxorubicin's one (IC50 ranged from 0.6 to 5.98 µM), but less toxic to normal and pseudonormal cells. All synthesized compounds were able to interact with DNA, although their anticancer activity did not correlate with the potency of interaction with DNA. The status of p53 in colorectal cancer cells correlated with the activity of the synthesized derivatives 3.1, 3.7, and 3.10. Compound 3.10 did not have an acute toxic effect on the body of С57BL/6 mice, unlike the well-known anticancer drug doxorubicin, which was used as a positive control. The injection of 3.10 (20 mg/kg) to mice had no effect on the counts of leukocytes, erythrocytes, platelets and hemoglobin level in their blood, in contrast to doxorubicin, which caused anemia and leukopenia, indicating bio-tolerance of 3.10in vivo.

4-thiazolidinone-based derivatives rosiglitazone and pioglitazone affect the expression of antioxidant enzymes in different human cell lines.

PPARγ regulate the expression of genes involved in peripheral insulin sensitivity, adipogenesis, and glucose homeostasis. Moreover, PPARγ agonists, such as pioglitazone and rosiglitazone, are used in the treatment of various diseases, e.g. diabetes (type II), atherosclerosis, inflammatory skin disease, and some types of cancers. PPARγ agonists have also been found to reduce oxidative-stress (OS) and OS-induced apoptosis. Therefore, the aim of the present study was to evaluate the impact of 4-thiazolidinone-based derivatives Les-2194, Les-3377, and Les-3640 on the expression of antioxidant enzymes in human squamous cell carcinoma (SCC-15), lung carcinoma (A549), colon adenocarcinoma (CACO-2), and skin fibroblast (BJ) cell lines. After 24 h of exposure, Les-2194 caused an increase in ROS production in the SCC-15 and CACO-2 cell lines; however, no changes in caspase-3 activity and metabolic activity were observed. Nevertheless, the Ki67 level was significantly decreased. Les-3377 was able to increase ROS production in all tested cell lines, but no impact on metabolic activity and caspase-3 activity were noticed. In turn, Les-3640 was able to induce ROS overproduction in BJ, SCC-15, and CACO-2 and did not affect metabolic activity. However, an increase in caspase-3 activity was observed at the 10 µM concentration in all tested cell lines. All tested compounds were able to influence CAT and SOD1 expression and decreased (Les-2194 in the BJ cells) or increased (Les-3640 in the SCC-15 and CACO-2 cells) PPARγ expression.

A facile synthesis and anticancer activity evaluation of spiro[thiazolidinone-isatin] conjugates.

The synthesis and evaluation of the anticancer activity of 3'-aryl-5'-arylidene-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones and spiro[3H-indole-3,2'-thi-azolidine]-2,4'(1H)-dione-3'-alkanoic acid esters were described. The structure of the compounds was determined by (1)H and (13)C NMR and their in vitro anticancer activity was tested in the National Cancer Institute. Among the tested compounds, (5'Z)-5'-(benzylidene)-3'-(4-chlorophenyl)spiro[3H-indole-3,2'-thia-zolidine]-2,4'(1H)-dione (IIa) and (5'Z)-3'-(4-chlorophenyl)-5'-[4-(1-methylethyl)-benzylidene]spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione (IIb) were superior to other related compounds.