Methyl-Thiol-Bridged Oxadiazole and Triazole Heterocycles as Inhibitors of NF-κB in Chronic Myelogenous Leukemia Cells

Abstract

Nuclear factor kappa beta (NF-κB) is a transcriptional factor that plays a crucial role in regulating cancer cell proliferation. Therefore, the inhibition of NF-κB activity by small molecules may be beneficial in cancer therapy. In this report, methyl-thiol-bridged oxadiazole and triazole heterocycles were synthesized via click chemistry and it was observed that the lead structure, 2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-(4-methoxybenzyl)-1,3,4-oxadiazole (4c), reduced the viability of MCF-7 cells with an IC50 value of 7.4 µM. Compound 4c also caused concentration-dependent loss of cell viability in chronic myelogenous leukemia (CML) cells. Furthermore, compound 4c inhibited the activation of NF-κB in human CML cells as observed by nuclear translocation and DNA binding assays. Functionally, compound 4c produced PARP cleavage and also suppressed expression of Bcl-2/xl, MMP-9, COX-2, survivin, as well as VEGF, resulting in apoptosis of CML cells. Moreover, ChIP assay showed that compound 4c decreased the binding of COX-2 to the p65 gene promoter. Detailed in silico analysis also indicated that compound 4c targeted NF-κB in CML cells. In conclusion, a novel structure bearing both triazole and oxadiazole moieties has been identified that can target NF-κB in CML cells and may constitute a potential novel drug candidate.

Synthesis of novel triazoles as anticancer agents targeting pJNK in human breast cancer cells

“…Evidently, triazolyl–oxadiazole compound E from our previous report has greater similarity to compound 5b , where the latter structure has an additional isopropyl group. 30 The IC 50 value of compound 5b was found to be lower than that of compound E , which could be because of the presence of a bis-triazole structure with an added isopropyl group. While other chloro/halo or alkyl derivatives were moderately active or inactive.…”

“…In our previous report, we reported the synthesis of triazolyl-oxadiazole I , as an anticancer agent. 30 To explore the structural diversity of the molecule we synthesized triazoles by forming a 1,2,4-triazole ring instead of a 1,3,4-oxadiazole ring and evaluated its anticancer activity targeting JNK in MCF-7 cells.…”

Electrochemical Synthesis of Versatile Pyrimidine and Oxadiazoles Tethered Triazoles as Inhibitors of VEGFR-2 in Human Breast Cancer Cells

“…Heterocycles have been widely studied and integrated into medicinal chemistry due to their diverse biological activities, including targeting specific cellular pathways, DNA binding, alkylation, and apoptosis induction [4,5]. Presently, extensive research is focusing on various natural and synthetic heterocyclic compounds, such as pyrimidines [6][7][8], coumarins [9,10], pyrazoles [11][12][13], triazoles [14][15][16], oxadiazoles [17][18][19], and piperazines [20,21], among others, which have displayed promising biological properties.…”