4-Bromo-2-(piperidin-1-yl)thiazol-5-yl-phenyl methanone (12b) inhibits Na+/K+-ATPase and Ras oncogene activity in cancer cells (original) (raw)
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The activity of a new 2-amino-1,3,4-thiadiazole derivative 4ClABT in cancer and normal cells
Folia Histochemica et Cytobiologica, 2011
The 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole set are well known compounds with interesting in vitro and in vivo anti-cancer profiles. The aim of this study was an in vitro evaluation of the anti-cancer activity of a new synthesized aminothiadiazole derivative 2-(3-chlorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole 4ClABT. The effect on tumor cell proliferation, motility and morphology, DNA synthesis as well as the influence on normal cells was assessed. The antiproliferative activity of 4ClABT in tumor cells derived from peripheral cancers including breast carcinoma (T47D), colon carcinoma (HT-29), thyroid carcinoma (FTC-238), teratoma (P19), and T-cell leukemia (Jurkat E6.1), as well as cancers of the nervous system including rhabdomyosarcoma/medulloblastoma (TE671), brain astrocytoma (MOGGCCM) and glioma (C6) was studied by means of MTT assay. DNA synthesis level was determined in BrdU ELISA test. Wound assay model was applied for tumor cell motility assessment. Morphological changes induced by 4ClABT in cancer and normal cells were analyzed in HE staining specimens. Moreover, the influence of 4ClABT on normal cells including skin fibroblasts (HSF), hepatocytes (Fao), astroglia and neurons was studied by means of LDH assay. The tested compound inhibited the proliferation of tumor cells in dose-dependent fashion. The anti-cancer effect was attributed to decreased DNA synthesis, prominent changes in tumor cell morphology as well as reduced cell motility. In antiproliferative concentrations, 4ClABT was not toxic to normal cells. Our study showed prominent anti-cancer effects of the tested aminothiadiazole derivative in the absence of toxicity in normal cells. The obtained results confirmed the promising anti-cancer profile of previously tested 2-(monohalogenphenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole derivatives (ClABT-chlorophenyl derivative, FABT and 3FABTfluorophenyl derivatives and 4BrABT-bromophenyl derivative). The molecular mechanisms and the in vivo activity of aminothiadiazole derivatives will be the subject of further studies.
In Vitro Growth Inhibition of U87 Glioblastoma Cells by N-(2- Hydroxy Phenyl) Acetamide
TJPRC, 2013
Despite the variety of modern therapies against glioblastoma, it is still a deadly disease with extremely poor prognosis. Patients have a median survival of approximately 12 to 15 months. The development of new therapeutic strategies for the management of gliomas is therefore crucial. The present study evaluates the therapeutic potentials of synthetic compound NA-2 in the treatment of GBM. Growth inhibitory effect of NA-2 on human glioblastoma cell line U87 was determined microscopically and by MTT assay. Apoptosis was detected by TUNEL assay. The RT-PCR was used to determine the mRNA level of vascular endothelial growth factor (VEGF) and hypoxia inducible factor- 1 alpha (HIF- 1α). Whereas protein level of VEGF is determined by ELISA. NA-2 significantly inhibits the growth of glioblastoma cells in a dose dependent manner (P < 0.01). Additionally it also significantly down regulates the expression of VEGF and HIF- 1α (P < 0.05). Our finding suggests that NA-2 possesses strong growth inhibitory activity which may in part be due to its ability to decrease expression levels of VEGF and HIF-1α.
Journal of Medicinal Chemistry, 2004
N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 {N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4piperidinecarboxamide, BMS-387032}, has been identified as an ATP-competitive and CDK2selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC 50) 48 nM and was 10-and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC 50) 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a sc/ip A2780 human ovarian carcinoma xenograft model.
Anticancer properties of 5Z-(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one
Scientific Reports, 2019
4-thiazolidinones, which are privileged structures in medicinal chemistry, comprise the well-known class of heterocycles and are a source of new drug-like compounds. Undoubtedly, the 5-bulkysubstituted-2,4-thiazolidinediones-a class of antihyperglycemic glitazones, which are peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are the most described group among them. As there are various chemically distinct 4-thiazolidinones, different subtypes have been selected for studies; however, their main pharmacological profiles are similar. The aim of this study was to evaluate the anticancer activity of 5Z-(4-fluorobenzylidene)-2-(4-hydroxyphenylamino)-thiazol-4-one (Les-236) in four human cancer cell lines, A549, SCC-15, SH-SY5Y, and CACO-2, and investigate its impact on the production of reactive oxygen species (ROS) and the apoptotic process as well as cytotoxicity and metabolism in these cell lines. The cell lines were exposed to increasing concentrations (1 nM to 100 µM) of the studied compound for 6, 24, and 48 h, and later, ROS production, cell viability, caspase-3 activity, and cell metabolism were examined. The obtained results showed that the studied compound decreased the production of ROS, increased the release of lactate dehydrogenase, and decreased cell metabolism/proliferation in all the five cell lines at micromolar concentrations. Interestingly, over a wide range of concentrations (from 1 nM to 100 µM), Les-236 was able to increase the activity of caspase-3 in BJ (after 6 h of exposure), A549, CACO-2, and SCC-15 (after 48 h of exposure) cell lines which could be an effect of the activation of PPARγ-dependent pathways. 4-thiazolidinones are a widely studied class of heterocycles, which are considered as privileged structures in medicinal chemistry, and a source of new drug-like compounds 1,2. Undoubtedly, the 5-bulky-substituted-2,4-thiazolidinediones, a class of antihyperglycemic glitazones, which are peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are the most described group among them 3. As there are various chemically distinct 4-thiazolidinones, different subtypes have been selected for investigations; however, their main pharmacological profiles are similar and they are known to exhibit anticancer, anti-inflammatory, antiviral, and antimicrobial activity. Moreover, different 4-thiazolidinones (2,4-thiazolidinone, rhodanine, 2-amino(imino)-4-thiazolidinone, etc.), and their related (hydantoin) cores are considered as bioisosteres. 5-ene-2-amino(imino)-4-thiazolidinones represent one of the most studied subtypes of 4-thiazolidinones. The importance of C5-ene fragment had been proved in many studies 4-6. Moreover, conjugation of the C5 exocyclic double bond to the C4 carbonyl group makes these compounds electrophilic and potentially reactive in Michael addition. This is one of the reasons why 5-ene-4-thiazolidinones, especially rhodanines, are called as pan-assay interference compounds 7-9. This concept is still under debate; however, many useful properties of Michael acceptors have been proposed 7,9,10 : Michael acceptors, among the most effective activators of Nrf2, open new perspectives in the treatment of inflammation and cancer 11. They act as inducers of phase 2 enzymes and a group of inducible proteins 12 and covalent inhibitors 13. Moreover, Michael acceptors function as reactive electrophilic species, one of the key signaling species 14 .
Na/K-ATPase as a target for anticancer drugs: studies with perillyl alcohol
Molecular Cancer, 2015
Background: Na/K-ATPase (NKA) is inhibited by perillyl alcohol (POH), a monoterpene used in the treatment of tumors, including brain tumors. The NKA α 1 subunit is known to be superexpressed in glioblastoma cells (GBM). This isoform is embedded in caveolar structures and is probably responsible for the signaling properties of NKA during apoptosis. In this work, we showed that POH acts in signaling cascades associated with NKA that control cell proliferation and/or cellular death.
Proapoptotic effects of novel thiazole derivative on human glioma cells
Anti-Cancer Drugs, 2018
The aim of the present study was to investigate the antiproliferative and proapoptotic actions of N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide derivative (compound 5) in glioma cells in comparison with the actions of temozolomide (TMZ) and doxorubicin (Dox), used as positive controls. The antiproliferative activity of the compound 5, TMZ, and Dox on human glioblastoma U251 and human glioblastoma multiform T98G cells was measured using the MTT test. Western blot analysis, fluorescent microscopy, agarose gel retardation assay, flow cytometric analysis, and the DNA comet assay under alkaline conditions were carried out to study the effect of compound 5 on U251 cells. This compound showed~20 times higher cytotoxicity toward U251 and T98G cells compared with the effects of TMZ and approximately two times higher activity than that of the Dox. Compound 5 induced apoptosis in U251 cells by PARP1 and caspase 3 cleavage mechanisms, also inducing an increase in the level of Bax and Bim proapoptotic proteins and a decrease in the level of phosho-ERK1/2 kinase. The cytotoxicity of compound 5 was associated with an increase in the production of the hydrogen peroxide and the formation of DNA single-strand breaks. This compound 5 did not intercalate into a DNA molecule. Thus, the novel thiazole derivative (compound 5) proved to be a potential antiglioma drug that showed much higher cytotoxic action on human glioma cells compared with the effects of TMZ and Dox. Its cytotoxicity is associated with apoptosis induction, production of the reactive oxygen species, and formation of DNA single-strand breaks without significant DNA intercalation.
Biochemical Pharmacology, 1982
Abstraet-Studies on the mechanism of action of a new oncolytic nucleoside, 2-P-D-rihofuranosylthiazoie-4-carboxamide, have been undertaken using P388 murine leukemia cells growing in culture. The title compound was cytotoxic at micromolar levels, but a number of simple substitutions of both the ring and sugar moieties nullified cytotoxicity. Cyto~uorimetric analysis revealed that the drug arrests cells in the "S phase" of the cel1 cycle. At antiproliferative concentrations, the agent inhibited the synthesis of both RNA and DNA. The macromolecular incorporation of preformed pyrimidines, including thymidine, was inhibited by the drug but, among the purines, this effect extended only to members of the adenine family and, in fact. the utilization of guanine and its congeners was reproducibly stimulated. When an examination was made of the ability of a comprehensive series of preformed purines and pyrimidines to overcome the inhibition of thymidine incorporation provoked by exposure to the thiazole nucleosidc, the guanines were notably effective. but xanthosine also was shown to be an active antidote. Confirmation that the drug was producing a state of guanine deprivation was provided by high performance liquid chromatography (HPLC) analysis of acid-soluble extracts: a time-dependent fall in the concentrations of GMP and GTP ensued upon exposure to the drug; on the other hand, IMP concentrations increased by -lS-fold. Pursuant to these findings, an examination was made of the enzymoiogic steps unique to the biosynthesis of guanine nucleotides in ceils exposed to cytotoxic concentrations of the drug. No prominent inhibition of GMP synthetase could be demonstrated in uirro or in culture, but the specific activity of IMP dehydrogenase underwent substantial reductions in both of these cases. HPLC analyses of extracts of cultures exposed to supralethal concentrations of the title compound provided evidence of modest anabolism to the 5'-monophosphate among other products; in oitro a chemically synthesized sample of 2-ED-ribofuranosyithiazole-4-carboxamide-5'monophosphate was twenty times more potent than the parent nucleoside in inhibiting IMP dehydrogenase. On kinetic analysis, this inhibition was non-competitive with IMP as the variable substrate.
Bioorganic & Medicinal Chemistry Letters, 2012
The anticancer potential of 2-amino-1,3,4-thiadiazole compounds has been documented by in vitro and in vivo studies. In our previous research, we described the synthesis as well as the antiproliferative and neuroprotective activities of 2-(4-fluorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (FABT). The aim of the present study was to investigate the molecular mechanisms involved in FABTinduced growth inhibition in A549 lung carcinoma cells. Western blotting analysis revealed that FABT inhibited the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, and Real-time PCR analysis showed no changes in the expression of P44ERK1 and CREB1 genes. Furthermore, FABT induced cell cycle arrest in the GO/G1 phase and enhanced p27/Kip1 expression. Our results suggest that FABT acts by inhibiting ERK1/2 pathway and cell cycle progression through G1 into S phase in A549 cells. Further studies are needed to completely explain the molecular mechanisms of anticancer action of this 2-aminothiadiazole derivative.
Antiproliferative and cytotoxic effects of some ?2 agonists and ?1 antagonists in tumour cell lines
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
To establish the activity of σ ligands at σ 1 and σ 2 receptor, we chose two tumour cell lines, the human SK-N-SH neuroblastoma and the rat C6 glioma lines, which express σ 2 receptors at a high density and σ 1 receptors in their high-affinity or low-affinity state. We tested the σ 2 receptor agonist PB28 and the σ 2 antagonist AC927, and (+)-pentazocine and NE100 as agonist and antagonist, respectively, at σ 1 receptors, with regard to antiproliferative and cytotoxic effects. In addition, 1,3-di (2-tolyl)guanidine (DTG) and haloperidol were tested as reference compounds displaying nearly equipotent σ affinity (σ 2 >σ 1 and σ 1 >σ 2 , respectively). In both SK-N-SH and C6 cells, PB28 and NE100 displayed the most potent results both in antiproliferative and cytotoxic assay while AC927 and (+)-pentazocine were inactive in both assays. The cytotoxic and antiproliferative effects of DTG and haloperidol reflected their σ 1 antagonist activity and σ 2 agonist activity. Moreover, our results in the tumour cell lines correlated well with those for σ 2 activity found previously in a functional assay in the guinea-pig bladder. These findings establish a new model for evaluating both σ 2 and σ 1 receptor activity of σ ligands, which could be useful for developing new ligands having mixed σ 2 agonist/σ 1 antagonist activity as potential antineoplastic agents.
Croatian Medical Journal, 2017
Aim To compare various pro-apoptotic effects of synthetic 4-thiazolidinone derivative (Les-3288), doxorubicin (Dox) and temozolomide (TMZ) in the treatment of human glioma U251 cells to improve treatment outcomes of glioblastoma and avoid anticancer drug resistance. Methods The cytotoxic effects of drugs used in human glioma U251 cells were measured by cell viability and proliferation assay (MTT), Trypan blue exclusion test, and Western-blot analysis of the apoptosis-related proteins. In addition, flow cytometry study of reactive oxygen species (ROS) level in glioma cells was carried out. Cytomorphological changes in treated cells were monitored by fluorescent microscopy after cell staining with Hoechst 33342 and ethydium bromide. Results Half-maximal inhibitory concentration (IC 50) of Les-3288, Dox, and TMZ was calculated for human glioblastoma U251 cells. The rating of the values of this indicator of cellular vitality was assessed. The results of MTT assay proved the superiority of Les-3288 vs Les-3288>Dox>TMZ, which is in agreement with the results of Trypan blue testing showing Les-3288 ≈ Dox>TMZ. In general, such ranking corresponded to a scale of pro-apoptotic impairments in the morphology of glioma U251 cells and the results of Western-blot analysis of cleaved Caspase 3. Contrary to Dox, Les-3288 and TMZ did not affect significantly ROS levels in the treated cells. Conclusion The effect of the synthetic 4-thiazolidinone derivative Les-3288 is realized via apoptosis mechanisms and does not involve ROS. In comparison with Dox and TMZ, it is more effective in destroying human glioblastoma U251 cells. Les-3288 compound has a potential as an anticancer drug for glioblastoma. Nevertheless, further preclinical studies of the blood-brain barrier are needed.