A range of hybrid molecules incorporating the ciminalum moiety in the thiazolidinone ring demonstrate significant anticancer and antimicrobial properties. Therefore, the aim of our study was to evaluate the properties and mechanism of action of two 4-thiazolidinone-based derivatives, i.e., 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (Les-45) and 5-[2-chloro-3-(4-nitrophenyl)-2-propenylidene]-2-(3-hydroxyphenylamino)thiazol-4(5H)-one (Les-247). In our study, we analyzed the impact of Les-45 and Les-247 on metabolic activity, caspase-3 activity, and the expression of genes and proteins related to inflammatory and antioxidant defenses and cytoskeleton rearrangement in healthy human fibroblasts (BJ) and a human lung carcinoma cell line (A549). The cells were exposed to increasing concentrations (1 nm to 100 μM) of the studied compounds for 24 h and 48 h. A decrease in the metabolic activity in the BJ and A549 cell lines was induced by both compounds at a concentration range from 10 to 100 μM. Both compounds decreased the mRNA expression of NRF2 (nuclear factor erythroid 2-related factor 2) and b-actin in the BJ cells. Interestingly, a significant decrease in the level of NF-kB gene and protein expression was detected in the BJ cell line, suggesting a direct impact of the studied compounds on the inhibition of inflammation. However, more studies are needed due to the ability of Les-45 and Les-247 to interfere with the tubulin/actin cytoskeleton, i.e., a critical system existing in eukaryotic cells.

Heterocycles are commonly known for their unique features, e.g., antibacterial or anticancer properties. Although many synthetic heterocycles, such as 4-thiazolidinone (4-TZD), have been synthesized, their potential applications have not yet been fully investigated. However, many researchers have reported relevant results that can be a basis for the search for new potential drugs. Therefore, the aim of this study was to evaluate the cytotoxic, cytostatic, and antibacterial effects of certain 4-thiazolidinone-based derivatives, Les-3166, Les-5935, Les-6009, and Les-6166, on human fibroblasts (BJ), neuroblastoma (SH-SY5Y), epithelial lung carcinoma (A549), and colorectal adenocarcinoma (CACO-2) cell lines in vitro. All tested compounds applied in a concentration range from 10 to 100 µM were able to decrease metabolic activity in the BJ, A549, and SH-SY5Y cell lines. However, the action of Les-3166 was mainly based on the ROS-independent pathway, similarly to Les-6009. In turn, Les-5935 and Les-6166 were able to promote ROS production in BJ, A549, and SH-SY5Y cells, compared to the control. Les-3166, Les-6009, and Les-6166 significantly increased the caspase-3 activity, especially at the concentrations of 50 µM and 100 µM. However, Les-5935 did not induce apoptosis. Only Les-5935 showed a minor cytostatic effect on SH-SY5Y cells. Additionally, the antibacterial properties of the tested compounds against P. aeruginosa bacterial biofilm can be ranked as follows: Les-3166 > Les-5935 > Les-6009. Les-6166 did not show any anti-biofilm activity. In summary, the study showed that Les-5935, Les-6009, and Les-6166 were characterized by anticancer properties, especially in the human lung cancer cell. In cases of BJ, SH-SY5Y, and CACO-2 cells the anticancer usage of such compounds is limited due to effect visible only at 50 and 100 µM.

Новину відредагував: library-lnmu - 2-01-2025, 10:25

UDC: 547.673.5+547.789.13

Synthesis and study of new polyfunctionalized 2-hydrazinoanthraquinone derivatives as potential antimicrobial agents. Methods. Organic synthesis, NMR and LC-MS spectroscopy, agar diffusion and broth microdilution methods. Results. A series of anthraquinonehydrazone derivatives are synthesized using the reaction of 2-(morpholinodiazenyl)anthracene-9,10-dione with methylene active compounds in the acetic acid medium. The screening of antimicrobial activity identified the compounds with significant effects against the tested microorganisms with MIC value <186.9 μM. Compounds 5 and 11 with MIC <93.5 μM are effective against yeast fungi whereas compound 5 with MIC <186.9 μM is effective against P.putida, which is multidrug resistant to antibiotics.

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. 

Purpose: Our study aimed to assess the effects of anticancer 4-thiazolidinone-based free water-insoluble therapeutics Les-3288 and
Les-3833 and their waterborne complexes with branched PEG-containing polymeric carriers (A24-PEG550 and A24-PEG750) on
immune response.
Methods: Human peripheral blood was used to study in vitro lymphocyte proliferative function, leukocyte phagocytic activity and
respiratory burst, and cytokine production.
Results: The binding of the polymer to the anticancer drug Les-3288, which is intended to mitigate the immunosuppressive effects of the
free drug on the proliferative activity of T lymphocytes and T-dependent B cells, demonstrated comparable efficacy for both A24-PEG750
and A24-PEG550 nanocarriers. Furthermore, it was observed that the drug-polymer complex significantly increased the reduced levels of
IFN-γ and TNF-α resulting from free Les-3288. Conversely, the reduced levels of IL-6 and IL-4 remained unchanged. Administration of
either form of Les-3288 had no effect on the phagocytic activity of monocytes, granulocytes or the respiratory burst of granulocytes. Due to
the reduced cell viability and increased cytotoxicity associated with Les-3833, tenfold lower doses were selected for the immune assays.
The effects of free Les-3833 on lymphocyte proliferative function resulted in significant stimulation of T-dependent B cells. The binding of
Les-3833 to the smaller carrier, A24-PEG550 was found to maintain the stimulatory effect on B lymphocytes. While no effect of free Les3833 on the granulocyte phagocytic activity was observed, binding of Les-3833 to both polymeric carriers resulted in a decrease in
granulocyte phagocytic activity and respiratory burst, with no observable effect on monocytes. Monitoring of cytokine production showed
no significant effect of either form of Les-3833 on the production of IFN-γ and IL-6. In the context of TNF-α and IL-4, the positive effect of
polymer binding on restoring suppressed cytokine levels induced by the Les-3833 free drug was slightly more favorable for A24-PEG750.
Conclusion: The drug complexation with novel PEGylated carriers is a promising way for efficient therapeutic development.
Keywords: anticancer compounds, lymphocytes, phagocytic activity, respiratory burst, cytokines