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Breast cancer (BC) is the second leading cause of cancer‐related mortality in women, and targeting biological pathways such as the JNK pathway has proven to be a viable therapeutic target for BC therapy. Here, we synthesized piperazin‐2‐yl‐pyrimidines and evaluated them for anticancer activity against MCF‐7 cells. In addition, antioxidant, reactive oxygen species (ROS) inhibition, caspase activity, and toxicity in platelets were studied in the presence and absence of active compound IA‐6 or IA‐7. Our detailed experimental analysis found that the compound IA‐7 showed anticancer activity by either activating p‐JNK or by inducing radical species in cancer and thrombosis model. Evident to in vitro analysis, the structure based molecular interaction studies of binding of IA‐7 to JNK3S exhibited a significant binding energy of −7.56 kcal/mol which was found to be a better binder when compared to previously reported JNK inducer (PC‐12). Overall, we herein report the analytically pure IA‐7 as lead structure that could be used as a template to develop target based anticancer agents where JNK modulation is predominant. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the second-largest cause of cancer-related deaths among women worldwide. The development of BC is a complex and multi-step process involving multiple cell types, creating a real challenge for the development of potential therapeutics against it. Several researchers have demonstrated that JNK family members have been associated with BC regulation and progression. In general, JNK is phosphorylated and activated by a number of upstream kinases, and phospho-JNK regulates a variety of cellular functions by phosphorylating c-Jun and other downstream targets. Thus, JNK has become a vital target for the development of potential therapeutics for BC treatment. In past years, electrosynthesis has emerged as a fascinating area superior to traditional chemical processes, as the evolved electrochemical technologies function at higher reaction rates for the synthesis of desired compounds. In this study, we have synthesized a series of triazole compounds using both conventional and electrochemical methods for targeting JNK in human BC cells. All the synthesized molecules were preliminarily evaluated for a cytotoxicity study against MCF-7 cells and the compound 1-(3,4-dichlorophenyl)-4-(((4-isopropyl-5-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)thio)methyl)-1H-1,2,3-triazole (5b) is the most potent candidate among the series based on its lower inhibition concentration (IC50) of 4.78 μM. Further studies were performed to evaluate the anticancer potential of novel 5b in human BC cells and the results showed that 5b significantly inhibited colony formation, migration and induced apoptosis by increasing the expression of pro-apoptotic protein BAX, and inhibiting the anti-apoptotic protein BCL2. Furthermore, the novel 5b also induced the phosphorylation of JNK in BC cells in a dose-dependent manner. Additionally, an in silico docking study revealed that compound 5b has a strong binding affinity (−8.88 kcal mol−1) towards JNK3S. In conclusion, the novel synthesized compound 5b triggers apoptosis and JNK phosphorylation in BC cells, and may provide a new and potent therapeutic strategy against BC. [ABSTRACT FROM AUTHOR]