A novel 4,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazole derivative inhibits tumor cell invasion and potentiates the apoptotic effect of TNF alpha by abrogating NF-kappa B activation cascade

作者：Ningegowda Raghu; Shivananju Nanjunda Swamy; Rajendran Peramiyan; Basappa; Rangappa Kanchugarakoppal S; Chinnathambi Arunachalam; Li Feng; Achar Raghu Ram; Shanmugam Muthu K; Bist Pradeep; Alharbi Sulaiman Ali; Lim Lina Hsiu Kim; Sethi Gautam; Priya Babu Shubha

来源：Apoptosis, 2017, 22(1): 145-157.

DOI：10.1007/s10495-016-1312-8

• Apoptosis
• TNFa
• NF-kB
• Invasion
• Thiadiazole

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-kappa B was one of the potential molecular targets modulated by DTTF. Specifically, the drug blocked the TNF alpha-induced phosphorylation of upstream I kappa B alpha kinase in a time-dependent manner leading to the suppression of NF-kappa B activation and nuclear translocation. DTTF also potentiated the apoptotic effect of TNF alpha, 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.

• 出版日期2017-1