Abstract
Cancer is a leading cause of death globally. Despite therapeutic advancements the mortality rate of cancer is continuously increasing. Thus, it is important to identify and design potential therapeutic agents which can specifically bind with most common targets of cancer and inhibit tumor progression. The present work discloses the potential therapeutic application of the novel 3,4-diaryl 1H-pyrazoles as prospective anti-cancerous agent. The in silico molecular docking studies performed with 3,4-disubstituted pyrazoles as ligand with targets including DNA, BCL-2 and F1-ATP Synthase revealed strong binding affinity with DNA (-7.5 kcal/mol), BCL-2 (-8.1 kcal/mol) and F1-ATP Synthase (-7.2 kcal/mol). Furthermore, the in silico finding was validated with the in vitro cytotoxicity assay with human breast cancer cell line (MDA-MB-231). MDA-MB-231 cells treated with 3,4-diarylpyrazole resulted in an increase in annexin-V positive cells, production of reactive oxygen species (ROS), dissipation of the mitochondrial membrane potential and activation of caspase-3. Taken together, this study demonstrate that a novel synthesized 3,4-diarylpyrazoles, showed strong binding affinity against DNA, anti-proliferative activity and executed apoptosis through ROS-dependent caspase-3-mediated mitochondrial intrinsic apoptotic pathway against MDA-MB-231 cells. These findings increase our understanding of the molecular mechanism (s) by which 3,4-diarylpyrazoles can exert their anticancer activity and may contribute towards development of novel therapeutic agent against breast cancer.
Highlights
The naturally occurring heterocyclic compounds along with their synthetic analogues are found to display a vast variety of biological activities [1, 2, 3, 4]
The synthesis involves the in situ formation of isoflavones under Pd-catalyzed reaction cross-coupling method performed with 3-trifloxychromone and triarylbismuth followed by reaction with hydrazine hydrate to furnish phenol substituted C-arylated pyrazoles in one pot operation in good to excellent yield
Whereas the known BCL-2 inhibitor, Navitoclax showed -8.9 kcal/mol binding affinity with BCL-2 (Figure 3), which is close to the diarylpyrazoles
Summary
The naturally occurring heterocyclic compounds along with their synthetic analogues are found to display a vast variety of biological activities [1, 2, 3, 4]. Celecoxib and Ruxolitinib are anti-inflammatory and anti-cancerous drugs respectively containing pyrazole scaffolds [7, 8] Apart from these examples, various other pyrazole based drugs are known in the literature and available in the market [4]. Liang and co-workers synthesized 4-Amino-(1H)-pyrazole derivatives and explored their efficacy as JAKs inhibitor comparable and some were found to be more potent than Ruxolitinib which is an approved anti-cancerous drugs [9]. Several other such novel pyrazoles derivatives are known to exhibit anti-cancerous activities [10]. Encouraged by the several such reports available in the literature about the effectiveness of pyrazole derivatives as potential anti-cancerous agents, the work reported explores the potential anti-cancerous activity of novel 3,4-diaryl pyrazoles
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