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. 2022 Jan 13;27(2):485.
doi: 10.3390/molecules27020485.

A New Series of Indeno[1,2- c]pyrazoles as EGFR TK Inhibitors for NSCLC Therapy

Ahmet Özdemir  1 , Halilibrahim Ciftci  2   3   4 , Belgin Sever  1   3 , Hiroshi Tateishi  3 , Masami Otsuka  2   3 , Mikako Fujita  3 , Mehlika Dilek Altıntop  1
Affiliations

A New Series of Indeno[1,2- c]pyrazoles as EGFR TK Inhibitors for NSCLC Therapy

Ahmet Özdemir et al. Molecules. .

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.

Keywords: anticancer activity; apoptosis; epidermal growth factor receptor; indenopyrazoles; microwave-assisted synthesis; non-small cell lung cancer; tyrosine kinases.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
The synthetic route for the preparation of compounds 1–7.
Figure 1
Figure 1
The inhibitory activity of the compounds on EGFR TK. (a) EGFR TK inhibition caused by compounds 1, 4, 7, and erlotinib at 30 μM concentration. (b) The EGFR TK inhibition of compound 4 and erlotinib at different concentrations. All descriptive data were expressed as the Mean ± Standard Deviation (SD). All experiments were repeated three times.
Figure 1
Figure 1
The inhibitory activity of the compounds on EGFR TK. (a) EGFR TK inhibition caused by compounds 1, 4, 7, and erlotinib at 30 μM concentration. (b) The EGFR TK inhibition of compound 4 and erlotinib at different concentrations. All descriptive data were expressed as the Mean ± Standard Deviation (SD). All experiments were repeated three times.
Figure 2
Figure 2
The inhibition of TKs by compound 4 and erlotinib at 30 μM concentration. All descriptive data were expressed as the Mean ± SD. All experiments were repeated three times.
Figure 3
Figure 3
The apoptotic effects of compound 4 and erlotinib on A549 cells. (a) Coloring phenomenon of the A549 cell line following exposure to IC50 concentrations of compound 4 and erlotinib for 15 h. (b) The percentage of apoptotic (green), necrotic or late apoptotic (both green and red), and necrotic (red) cells was quantified by analyzing 100 randomly chosen stained cells in each experiment. All descriptive data were expressed as the Mean ± SD. All experiments were repeated three times.
Figure 4
Figure 4
Docking poses of compound 4, compound 1, and erlotinib (a) (colored in orange, blue purple, and turquoise, respectively) (green dashes: π-cation interaction, yellow dashes: hydrogen bonding) and docking interactions of compound 4, compound 1, and erlotinib (b) in the ATP binding site of EGFR.
Figure 4
Figure 4
Docking poses of compound 4, compound 1, and erlotinib (a) (colored in orange, blue purple, and turquoise, respectively) (green dashes: π-cation interaction, yellow dashes: hydrogen bonding) and docking interactions of compound 4, compound 1, and erlotinib (b) in the ATP binding site of EGFR.
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