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

Bar, Monika; Skóra, Bartosz; Tabęcka-Łonczyńska, Anna; Holota, Serhii; Khyluk, Dmytro; Roman, Olexandra; Lesyk, Roman; Szychowski, Konrad A.

doi:10.1016/j.bioorg.2022.106075

Cited by 12 publications

(6 citation statements)

References 57 publications

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“…Our results suggest a greater impact of Les-3467 on metabolic activity than Les-4369. As reported by Bar et al (2022), 4-TZD derivatives, such as Les-2769 and Les-3266 ( Figure 4 ), decreased the metabolic activity in BJ and SCC-15 cells [ 37 ]. Skóra et al (2022) described a decrease in metabolic activity in BJ and A549 cells after 24 and 48 h exposure to Les-3166, Les-5935, Les-6166, and Les-6009 ( Figure 4 ) [ 39 ].…”

Section: Resultssupporting

confidence: 55%

“…In turn, an increase in the LDH release level in high micromolar concentrations of the tested compounds indicates cell death. Similarly, Bar et al showed that other 4-TZD derivatives, such as Les-2769 and Les-3266, increased LDH release mainly at high concentrations in SCC-15 cells [ 37 ]. Finiuk et al (2023) reported increased LDH release from SCC-15 cells treated with high concentrations of Les-6287, Les-6294, and Les-6328 [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

“…The changes in the PPARG mRNA expression in the BJ cells caused by both compounds and in the A549 cells exposed to Les-4369 may indicate an impact of Les-3467 and Les-4369 on the PPARγ pathway. Bar et al (2022) described an increase in PPARG mRNA expression in BJ cells after 10 μM Les-3266 treatment [ 37 ]. Interestingly, Szychowski et al (2022) demonstrated increased PPARG mRNA expression caused by 10 μM Les-236 in the same cell line and obtained similar results in the A549 cell line [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

“…As a result of OS, the PPARγ-AhR crosstalk may regulate the expression of CAT and SOD in cells [ 19 , 35 , 36 ]. Last but not least, the impact of the new 4-TZD-based molecules on PPARγ and their possible agonist properties have been shown in different human cell lines, such as normal fibroblast (BJ), squamous cell carcinoma (SCC-15), lung carcinoma (A549), colon adenocarcinoma (CACO-2), and neuroblastoma (SH-SY5Y) cells [ 13 , 37 , 38 , 39 ]. The new 4-TZD derivatives should be investigated given the promising anticancer properties of these compounds presented in the available literature [ 13 , 14 , 37 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

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Role of 4-Thiazolidinone–Pyrazoline/Indoline Hybrids Les-4369 and Les-3467 in BJ and A549 Cell Lines

Kosińska,

Skóra,

Holota

et al. 2024

Cells

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Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to bind peroxisome proliferator receptor γ (PPARγ), which has various effects on cancer and can inhibit cell proliferation. In this study, we investigated the effect of new 4-thiazolidinone (4-TZD) hybrids Les-4369 and Les-3467 and their effect on reactive oxygen species (ROS) production, metabolic activity, lactate dehydrogenase (LDH) release, caspase-3 activity, and gene and protein expression in human foreskin fibroblast (BJ) cells and lung adenocarcinoma (A549) cells. The ROS production and caspase-3 activity were mainly increased in the micromolar concentrations of the studied compounds in both cell lines. Les-3467 and Les-4369 increased the mRNA expression of PPARG, P53 (tumor protein P53), and ATM (ATM serine/threonine kinase) in the BJ cells, while the mRNA expression of these genes (except PPARG) was mainly decreased in the A549 cells treated with both of the tested compounds. Our results indicate a decrease in the protein expression of AhR, PPARγ, and PARP-1 in the BJ cells exposed to 1 µM Les-3467 and Les-4369. In the A549 cells, the protein expression of AhR, PPARγ, and PARP-1 increased in the treatment with 1 µM Les-3467 and Les-4369. We have also shown the PPARγ modulatory properties of Les-3467 and Les-4369. However, both compounds prove weak anticancer properties evidenced by their action at high concentrations and non-selective effects against BJ and A549 cells.

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of 4-Thiazolidinone–Pyrazoline/Indoline Hybrids Les-4369 and Les-3467 in BJ and A549 Cell Lines

Kosińska,

Skóra,

Holota

et al. 2024

Cells

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“…Thiazolidine derivatives can potentially target cancer cells with altered glucose utilization, leading to metabolic stress and cell death [ 17 ]. Moreover, these compounds exhibit anti-inflammatory properties [ 18 , 19 ], which can suppress tumor-promoting inflammation and contribute to their anticancer activity [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Derivatives Incorporating Acridine, Pyrrole, and Thiazolidine Rings as Promising Antitumor Agents

Garberová,

Potočňák,

Tvrdoňová

et al. 2023

Molecules

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Derivatives combining acridine, pyrrole, and thiazolidine rings have emerged as promising candidates in the field of antitumor drug discovery. This paper aims to highlight the importance of these three structural motifs in developing potent and selective anticancer agents. The integration of these rings within a single molecule offers the potential for synergistic effects, targeting multiple pathways involved in tumor growth and progression. Spiro derivatives were efficiently synthesized in a two-step process starting from isothiocyanates and 2-cyanoacetohydrazide. The thiourea side chain in spiro derivatives was utilized as a key component for the construction of the thiazolidine-4-one ring through regioselective reactions with bifunctional reagents, namely methyl-bromoacetate, dietyl-acetylenedicarboxylate, ethyl-2-bromopropionate, and ethyl-2-bromovalerate. These reactions resulted in the formation of a single regioisomeric product for each derivative. Advanced spectroscopic techniques, including 1D and 2D NMR, FT-IR, HRMS, and single-crystal analysis, were employed to meticulously characterize the chemical structures of the synthesized derivatives. Furthermore, the influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. Notably, derivatives containing ester functional groups exhibited exceptional activity against all tested cancer cell lines, boasting IC50 values below 10 μM. Particularly striking were the spiro derivatives with methoxy groups at position 3 and nitro groups at position 4 of the phenyl ring. These compounds displayed remarkable selectivity and exhibited heightened activity against HCT-116 and Jurkat cell lines. Additionally, 4-oxo-1,3-thiazolidin-2-ylidene derivatives demonstrated a significant activity against MCF-7 and HCT-116 cancer cell lines.

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Evaluation of thiopyrano[2,3‐d]thiazole derivatives as potential anticonvulsant agents

Davydov,

Hoidyk,

Shtrygol'

et al. 2024

Archiv der Pharmazie

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Anticonvulsant drug discovery has achieved significant progress; however, pharmacotherapy of epilepsy continues to be a challenge for modern medicine and pharmacy. To expand the chemical space of heterocycles as potential antiepileptic agents, herein we report on the synthesis and evaluation of anticonvulsant properties of a series of thiopyrano[2,3‐d]thiazoles. The studied heterocycles are characterized by satisfactory drug‐likeness and pharmacokinetics properties, calculated in silico using SwissADME. The anticonvulsant activity of thiopyrano[2,3‐d]thiazole derivatives was evaluated in vivo using the subcutaneous pentylenetetrazole test. Three hits, that is, compounds 12, 14, and 16, that caused a pronounced anticonvulsant effect were identified. Derivatives 12, 14, and 16 positively affected the latent period of onset of clonic seizures, number of seizures, mortality rate, and duration of the seizure period of animals under experimental conditions. The anticonvulsant properties of compound 14 were equivalent to the effect of the reference drug, sodium valproate. All hit compounds are characterized by satisfying toxicity properties in the human lymphocytes and HEK293 cell line. The most active hit 14 possesses a potential affinity with the GABAA receptor in the molecular docking study and forms a stable complex in the molecular dynamics experiments equal to diazepam. Preliminary SAR results were obtained and discussed based on screening data.

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

Cited by 12 publications

References 57 publications

Role of 4-Thiazolidinone–Pyrazoline/Indoline Hybrids Les-4369 and Les-3467 in BJ and A549 Cell Lines

Role of 4-Thiazolidinone–Pyrazoline/Indoline Hybrids Les-4369 and Les-3467 in BJ and A549 Cell Lines

Derivatives Incorporating Acridine, Pyrrole, and Thiazolidine Rings as Promising Antitumor Agents

Evaluation of thiopyrano[2,3‐d]thiazole derivatives as potential anticonvulsant agents

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