Cytotoxic Evaluation and Molecular Docking Studies of Aminopyridine Derivatives as Potential Anticancer Agents.

BACKGROUND: The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate for this therapeutic failure. OBJECTIVES: The current study demonstrated whether N-protected and deprotected amino acid derivatives of 2- aminopyridine could attenuate tumor development using colorectal cancer cell lines. METHODS: Biological assays were performed to investigate the anticancer potential of synthesized compounds. The in silico ADME profiling and docking studies were also performed by docking the designed compounds against the active binding site of beta-catenin (CTNNB1) to analyze the binding mode of these compounds. Four derivatives 4a, 4b, 4c, and 4d were selected for investigation of in vitro anticancer potential using colorectal cancer cell line HCT 116. The anti-tumor activities of synthesized compounds were further validated by evaluating the inhibitory effects of these compounds on the target protein beta-catenin through in vitro enzyme inhibitory assay. RESULTS: The docking analysis revealed favorable binding energies and interactions with the target proteins. The in vitro MTT assay on colorectal cancer cell line HCT 116 and HT29 revealed potential anti-tumor activities with an IC50 range of 3.7-8.1µM and 3.27-7.7 µM, respectively. The inhibitory properties of these compounds on the concentration of beta-catenin by ELISA revealed significant percent inhibition of target protein at 100 µg/ml. CONCLUSION: In conclusion, the synthesized compounds showed significant anti-tumor activities both in silico and in vitro, having potential for further investigating its role in colorectal cancer.

NF-κB Inhibitors Attenuate MCAO Induced Neurodegeneration and Oxidative Stress-A Reprofiling Approach.

Stroke is the leading cause of morbidity and mortality worldwide. About 87% of stroke cases are ischemic, which disrupt the physiological activity of the brain, thus leading to a series of complex pathophysiological events. Despite decades of research on neuroprotectants to probe for suitable therapies against ischemic stroke, no successful results have been obtained, and new alternative approaches are urgently required in order to combat this pathological torment. To address these problems, drug repositioning/reprofiling is explored extensively. Drug repurposing aims to identify new uses for already established drugs, and this makes it an attractive commercial strategy. Nuclear factor-kappa beta (NF-κB) is reported to be involved in many physiological and pathological conditions, such as neurodegeneration, neuroinflammation, and ischemia/reperfusion (I/R) injury. In this study, we examined the neuroprotective effects of atorvastatin, cephalexin, and mycophenolate against the NF-κB in ischemic stroke, as compared to the standard NF-κB inhibitor caeffic acid phenethyl ester (CAPE). An in-silico docking analysis was performed and their potential neuroprotective activities in the in vivo transient middle cerebral artery occlusion (t-MCAO) rat model was examined. The percent (%) infarct area and 28-point composite neuro score were examined, and an immunohistochemical analysis (IHC) and enzyme-linked immunosorbent assay (ELISA) were further performed to validate the neuroprotective role of these compounds in stroke as well as their potential as antioxidants. Our results demonstrated that these novels NF-κB inhibitors could attenuate ischemic stroke-induced neuronal toxicity by targeting NF-κB, a potential therapeutic approach in ischemic stroke.