title: A novel 4,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazole derivative inhibits tumor cell invasion and potentiates the apoptotic effect of TNFα by abrogating NF-κB activation cascade.
abstract: Condensed-bicyclic 4,6-substituted1,2,4-triazolo-1,3,4-thiadiazole derivatives (CBTT) have been shown to possess a wide spectrum of pharmacological activities. In this study, several novel CBTT derivatives were synthesized and investigated for their possible role as anti-neoplastic agents. The anti-proliferative effect of various CBTT derivatives was analyzed against tumor cell lines by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay. One of the potential CBTT derivative, 5-(3-(2,3-dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)flurobenzonitrile (DTTF) was found to be the most potent against cervical cancer SiHa cells and exhibited minimal effect against normal cells. Molecular docking analysis indicated that transcription factor NF-κB was one of the potential molecular targets modulated by DTTF. Specifically, the drug blocked the TNFα-induced phosphorylation of upstream IκBα kinase in a time-dependent manner leading to the suppression of NF-κB activation and nuclear translocation. DTTF also potentiated the apoptotic effect of TNFα, as well as significantly inhibited migration and invasion of tumor cells. Overall, these findings indicate a potential novel role and mechanism(s) of action of DTTF as an anticancer agent against diverse malignancies.
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India.
authors.forename: Raghu
authors.initials: R
authors.lastname: Ningegowda
authors.affiliation: Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, 570006, Karnataka, India.
authors.forename: Nanjunda Swamy
authors.initials: NS
authors.lastname: Shivananju
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
authors.forename: Peramiyan
authors.initials: P
authors.lastname: Rajendran
authors.affiliation: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore, 560001, Karnataka, India.
authors.lastname: Basappa
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, India.
authors.forename: Kanchugarakoppal S
authors.initials: KS
authors.lastname: Rangappa
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.
authors.forename: Arunachalam
authors.initials: A
authors.lastname: Chinnathambi
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Biotechnology, JSS Science and Technology University, JSS Technical Institutions Campus, Mysore, 570006, Karnataka, India.
authors.forename: Raghu Ram
authors.initials: RR
authors.lastname: Achar
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: Department of Physiology, Centre for Life Sciences, NUHS, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bist
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.
authors.forename: Sulaiman Ali
authors.initials: SA
authors.lastname: Alharbi
authors.affiliation: Department of Physiology, Centre for Life Sciences, NUHS, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore.
authors.forename: Lina Hsiu Kim
authors.initials: LHK
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore. phcgs@nus.edu.sg.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India. priyabs_chem@yahoo.com.
authors.forename: Babu Shubha
authors.initials: BS
authors.lastname: Priya
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000235:genetics*; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000737:chemistry / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000008:administration & dosage / Q000737:chemistry; D051996:Transcription Factor RelA / Q000737:chemistry / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D016328:NF-kappa B; C498143:RELA protein, human; C439524:TNF protein, human; D013830:Thiadiazoles; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C058949:1,3,4-thiadiazole; D051550:I-kappa B Kinase
keywords: Apoptosis; Invasion; NF-kB; TNFa; Thiadiazole