Enhanced Proapoptotic Effects of Water Dispersed Complexes of 4-Thiazolidinone-Based Chemotherapeutics with a PEG-Containing Polymeric Nanocarrier.

AIM: To study whether water formulation of the complex of 4-thiazolidinone derivatives with a PEG-containing polymeric nanocarrier enhances their pro-apoptotic action towards rat glioma C6 cells. METHODS: Mechanisms of antineoplastic effects of 4-thiazolidinone derivatives were investigated in vitro with rat glioma C6 cells. Cell nativity, cell cycling pattern, and Annexin V expression were evaluated and DNA damage was estimated by DNA comet analysis. A novel water-based formulation of 4-thiazolidinone derivatives complexed with a polymeric nanocarrier was utilized for enhancing pro-apoptotic action towards C6 cells. RESULTS: The studied 4-thiazolidinone derivatives use apoptosis mechanisms for killing rat glioma C6 cells, as confirmed by FACS analysis of these cells in pre-G1 stage, the appearance of Annexin V positive C6 cells, and an increased number of DNA comets of higher classes. Complexation of the studied compounds with a PEG-containing polymeric nanocarrier significantly increased pro-apoptotic effects in rat glioma C6 cells measured by all methods mentioned above. CONCLUSION: Complexation of 4-thiazolidinone derivatives with a PEG-containing polymeric nanocarrier provided them with water solubility and enhanced pro-apoptotic effects in rat glioma C6 cells.

Biochemical indicators of nephrotoxicity in blood serum of rats treated with novel 4-thiazolidinone derivatives or their complexes with polyethylene glycol-containing nanoscale polymeric carrier

The aim of this study was to compare the effect of new synthetic 4-thiazolidinone derivatives (potential anticancer compounds denoted as 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethylene glycol-containing nanoscale polymeric carrier on the biochemical indicators of nephrotoxicity in blood serum of rats. The concentration of total protein, urea, creatinine, glucose, ions of sodium, potassium, calcium, iron and chloride was measured. It was found that after injection of the investigated compounds, the concentration of sodium cations and chloride anions in blood serum was increased compared with control (untreated animals). Doxorubicin's injection was accompanied by a decrease in the concentration of iron cations. The concentration of total protein, urea and creatinine decreased under the influence of the studied compounds. Complexation of these аntineoplastic substances with a synthetic polymeric nanocarrier lowered the concentration of the investigated metabolites substantially compared to the effect of these compounds in free form. The normalization of concentration of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with the polymeric carrier comparing with increased concentration of these indicators at the introduction of such compounds in free form was found.

BIOCHEMICAL INDICATORS OF HEPATOTOXICITY IN BLOOD SERUM OF RATS UNDER THE EFFECT OF NOVEL 4-THIAZOLIDINONE DERIVATIVES AND DOXORUBICIN AND THEIR COMPLEXES WITH POLYETHYLENEGLYCOL-CONTAINING NANOSCALE POLYMERIC CARRIER.

The aim of this study was to compare the effect of new synthetic 4-tiazolidinone derivatives (compounds 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethyleneglycol-containing nanoscale polymeric carrier on the biochemical indicators of hepatotoxicity in blood serum of rats. The activity of enzymes considered as the markers of hepatotoxicity, as well as. the concentration of total protein, urea and creatinine were measured in blood serum of rats. It was found that after injection of investigated compounds the activities ofalanine aminotransferase, alkaline phosphatase and α-amylase increased in comparison to control. Doxorubicin injection was accompanied by 4-fold increase in the activity of γ-glutamyltransferase, and injection ofcompound 3833 led to 2.5-fold elevation ofthe activity of this enzyme. Complexation ofthese antineoplastic derivatives with a synthetic nanocarrier lowered the activity ofthe investigated enzymes substantially if compared to the effect of these compounds infreeform. The most evident decrease was measured for α-amylase, γ-glutamyltransferase and lactate dehydrogenase activities. The normalization of concentrations of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with a polymeric carrier comparing with their introduction infreeform was also detected. Thus, the immobilization by novel polymeric carrier of anticancer drugs possessing high general toxicity in the treated organism mitigates their toxic effect, which is evident as normalization of specific biochemical indicators of the hepatodestructive effects of the anticancer drugs.

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

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.

2-[7-(3,5-Dibromo-2-hy-droxy-phen-yl)-6-eth-oxy-carbonyl-2-oxo-5H-2,3,6,7-tetra-hydro-thio-pyrano[2,3-d][1,3]thia-zol-6-yl]acetic acid ethanol monosolvate.

The title compound, C(17)H(15)Br(2)NO(6)S(2)·C(2)H(5)OH, is the esterification reaction product of 2-(8,10-dibromo-2,6-dioxo-3,5,5a,11b-tetra-hydro-2H,6H-chromeno[4',3':4,5]thio-pyrano[2,3-d]thia-zol-5a-yl)acetic acid. Cleavage of the lactone ring and formation of eth-oxy-carbonyl and hy-droxy groups from its structural elements were observed. On the other hand, the carb-oxy-methyl group was not esterified. The H atom and carb-oxy-methyl group, both at stereogenic centres, show a cis conformation. The six-membered dihydro-thio-pyran ring adopts a half-chair conformation. All NH and OH groups participate in the three-dimensional hydrogen-bond network, which is additionally strengthened by C-H⋯O and C-H⋯S inter-actions. Intramolecular O-H⋯Br and C-H⋯O interactions also occur.

Synthesis and antiinflammatory activity of novel 3-(2,3-dimethyl-1-phenyl-4-pyrazolon-5-yl)-4-thiazolidones.

New 3-(2,3-dimethyl-1-phenyl-4-pyrazolon-5-yl)-4-thiazolidones were synthesized. The structure of substances was supported by UV- and 1H-NMR spectra. Some compounds were tested in vivo for their antiinflammatory activity. Were confirmed previous results about structure-activity relationships.

New thiazolidones-4 with pyrazolone-5 substituent as the potential NSAIDs.

The synthesis of a group of thiazolidine derivatives with pyrazolone-5 substituent is described. The structure of the new compounds is supported by 1H- and 13C-NMR spectra. Group of compounds was tested in vivo for their antiinflammatory activity. The obtained results gave the opportunity to separate the perspective groups of potential NSAIDs, which have got greater antiinflammatory activity than the best standard drugs.