NRC-2694

Cervical cancer is the fourth most common cancer among women globally. Its development is closely linked to accelerated cell cycle progression and the inhibition of apoptosis in cervical cancer tissues. Gefitinib has demonstrated efficacy in inhibiting cervical cancer cells, and the 1,2,3‐triazole structure is widely recognized for its role in inducing mitochondrial apoptosis in tumor cells. In this study, we employed click chemistry to modify the structure of gefitinib, leading to the synthesis of 16 derivatives containing the 1,2,3‐triazole moiety. These compounds were evaluated for their in vitro activity against Hela cells. Among them, compound 3p exhibited the most promising anticancer activity, with an IC 50 value of 4.09 ± 0.54 μM. Compound 3p significantly inhibited Hela cell colony formation in a dose‐dependent manner, accompanied by noticeable morphological changes. Further investigations revealed that 3p induced apoptosis and caused G2/M phase cell cycle arrest in Hela cells. Western blot analysis showed that 3p increased the Bax/Bcl‐2 ratio and elevated the levels of cleaved caspase‐3 and PARP1, indicating that apoptosis was mediated through the mitochondrial pathway. Additionally, 3p inhibited indoleamine 2,3‐dioxygenase 1 (IDO1) enzymatic activity, and molecular docking studies revealed a strong interaction between 3p and the IDO1 active site, suggesting that IDO1 may be a potential target. In conclusion, compound 3p shows promise as a potential therapeutic agent for cervical cancer.

In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC50) values of 4b were 4.42 ± 0.24 μM (NCI-H1299), 3.94 ± 0.01 μM (A549) and 1.56 ± 0.06 μM (NCI-1437). The IC50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 μM (A549) and 3.51 ± 0.05 μM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment.