title: 1,2,4-Thiadiazolidine derivative inhibits nuclear transcription factor-kappaB and its dependent genes activation but induces apoptosis.
abstract: The 1,2,4-thiadiazolidine derivatives have been shown to be involved in several biological responses such as anti-bacterial, anti-fungal, anti-tubercular and local anaesthetic activities. In our study, we have synthesized some new 5-substitutedarylimino-2-N-substitutedphenyl-3-oxo-1,2,4-thiadiazolidine and tested for anti-inflammatory and anti-tumor activities. The 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-Oxo-1,2,4-thiadiazolidine (P(3)-25) showed anti-inflammatory activity as it inhibited different inflammatory inducers mediated nuclear transcription factor kappa B (NF-kappaB), a key transcription factor involved in all forms of inflammation. P(3)-25 inhibited TNF-induced NF-kappaB activation as detected by gel shift assay and dependent reporter gene expression. It inhibited IkappaBalpha degradation, IkappaB kinase activation and p65 nuclear translocation. P(3)-25 inhibited TNF-induced Cox2 expression. It inhibited NF-kappaB activation in human epithelial and T cells. Unlike other substitutary derivatives, P(3)-25 was a potent inducer of apoptosis as it induced cell death, caspase-dependent PARP cleavage, ROI generation and lipid peroxidation. Overall our results suggest that P(3)-25 derivative exerts anti-inflammatory and anti-tumor activities, which may have a role in designing such drugs.
authors.affiliation: Department of Applied Chemistry, Institute of Technology, Banaras Hindu University, Varanasi, India.
authors.forename: Paresh
authors.initials: P
authors.lastname: Manna
authors.forename: Krishnan K
authors.initials: KK
authors.lastname: Narang
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Manna
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D021381:Protein Transport; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013830:Thiadiazoles; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C495275:5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D013830:Thiadiazoles; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020169:Caspases