Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC.
Highlights
Non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancers, represents the most common cause of cancer-related mortality worldwide [1,2], with a 5-year survival rate of less than 15% [3]
The Infrared (IR), 1H Nuclear Magnetic Resonance (NMR), 13C NMR, and HighResolution Mass Spectrometry (HRMS) data were in agreement with the proposed structures of compounds 1–7
The formation of the dihydroindenopyrazole3 of 15 scaffold was verified by the HRMS analysis of compounds 1–7
Summary
Non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancers, represents the most common cause of cancer-related mortality worldwide [1,2], with a 5-year survival rate of less than 15% [3]. Most NSCLC patients are diagnosed at advanced or metastatic stages (stage III/IV), when surgery is no longer an option. In these cases, radiotherapy and chemotherapy are important therapeutic approaches for unresectable NSCLC [4,5,6,7]. Platinum-based chemotherapy is an existing Food and Drug Administration (FDA)approved strategy in the management of several common cancer types, including NSCLC, and has many benefits in some cases [8,9]. Traditional cytotoxic chemotherapy causes changes in the normal function of the cells, and correspondingly various side effects such as fatigue, anemia, alopecia, and gastrointestinal complications [8,9,10]
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