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.

A series of 20 novel gefitinib derivatives incorporating the 1,2,3-triazole moiety were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H1299, A549) and human lung adenocarcinoma cells (NCI-H1437) as non-small cell lung cancer. In comparison to gefitinib, Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds 7a and 7j demonstrated the most pronounced effects, with an IC₅₀ value of 3.94 ± 0.17 µmol L⁻¹ (NCI-H1299), 3.16 ± 0.11 µmol L⁻¹ (A549), and 1.83 ± 0.13 µmol L⁻¹ (NCI-H1437) for 7a, and an IC₅₀ value of 3.84 ± 0.22 µmol L⁻¹ (NCI-H1299), 3.86 ± 0.38 µmol L⁻¹ (A549), and 1.69 ± 0.25 µmol L⁻¹ (NCI-H1437) for 7j. These two compounds could inhibit the colony formation and migration ability of H1299 cells, and induce apoptosis in H1299 cells. Acute toxicity experiments on mice demonstrated that compound 7a exhibited low toxicity in mice. Based on these results, it is proposed that 7a and 7j could potentially be developed as novel drugs for the treatment of lung cancer.

Introduction: The development of novel targeted therapies for hepatocellular carcinoma remains a critical need in oncology. This study aimed to design and evaluate a new series of triazole-urea hybrid compounds for their anti-cancer potential. Methods: A series of urea compounds bearing terminal alkynyl groups were synthesized via an assembly and post-modification strategy. Subsequent Click chemistry yielded the novel triazole-urea hybrids ( 3a– 3e, 5a– 5e, 7a– 7e). Their anti-proliferative effects were assessed against multiple human cancer cell lines (lung: H460, H1299, A549, PC-9; liver: Huh-7; breast: MCF-7) and normal liver cells (L02) using the CCK-8 assay. Mechanisms were investigated through apoptosis, autophagy, and DNA damage assays. An acute oral toxicity study was conducted in female KM mice at a dose of 500 mg/kg, with thorough monitoring of body weight, organ coefficients, and histopathology of major organs. Results: Most compounds exhibited potent, concentration- and time-dependent anti-proliferative activity against Huh-7 liver cancer cells, with only marginal effects on other tested cancer lines. Crucially, no cytotoxicity was observed in normal L02 cells. Mechanistic studies revealed that the lead compound induced apoptosis, autophagy, and DNA damage in Huh-7 cells. The in vivo assay demonstrated no drug-related mortality or significant adverse effects on body weight, organ coefficients, or histology at 500 mg/kg over 14 days, indicating a high maximum tolerated dose and an excellent preliminary safety profile. Conclusion: These findings demonstrate the selective anti-liver cancer efficacy and favorable in vivo safety of these triazole-urea hybrids, particularly compound 3c, underscoring their strong potential as promising therapeutic candidates for hepatocellular carcinoma.

This study explores the anticancer potential of rigid planar compounds capable of intercalating into tumor cell DNA, thereby inducing DNA damage and subsequent cell death. A novel series of compounds (c1–c20) were synthesized using 2H-1,4-benzoxazin-3(4H)-one as the planar core structure, with 1,2,3-triazole groups introduced at the 7-position. Biological evaluation across multiple human tumor cell lines revealed that several c-series compounds exhibited notable inhibitory activity against Huh-7 liver cancer cells, with IC₅₀ values of 28.48 μM (c5), 32.60 μM (c14), 31.87 μM (c16), and 19.05 μM (c18). Mechanistic studies indicated that these compounds effectively induced DNA damage, as evidenced by the upregulation of γ-H2AX, and triggered apoptosis via increased caspase-7 expression. Moreover, enhanced LC3 expression and autophagosome formation suggested the activation of autophagy pathways. The observed biological activities are likely attributed to the rigid planar configuration of the molecules, which facilitates DNA intercalation. Collectively, these results highlight the potential of these synthesized compounds as promising lead candidates for the development of novel therapeutic agents against liver cancer. Importantly, acute toxicity studies in mice demonstrated that these compounds possess favorable safety profiles, further supporting their potential for future preclinical development.

In the search for novel anticancer agents, a series of triazole–urea hybrids were designed and synthesized. Among them, compound 5a exhibited potent and selective cytotoxicity against hepatocellular carcinoma (HCC) cells, displaying an IC₅₀ value of 8.32 ± 1.26 μM against the Huh-7 cell line, while exerting minimal effects on other cancer cell lines and normal hepatocytes (LO2). Mechanistic investigations revealed that 5a triggers DNA damage and activates autophagy, which collectively contribute to the suppression of cell proliferation and the induction of dose-dependent apoptosis. Taken together, 5a represents a promising lead compound for the development of novel anti-HCC therapeutics, warranting further in-depth evaluation.

Targeted cancer drug therapy has emerged as a critical treatment modality for advanced hepatocellular carcinoma (HCC). The discovery and development of novel anti-HCC drug therapeutics with improved pharmacological properties remains an urgent priority in oncology drug discovery. In this study, we designed and synthesised a new series of 1,2,3-triazole-cored structures incorporating aryl urea. Fifteen analogs were prepared via nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. These synthesised compounds were evaluated for their potential antitumor activities. Notably, compounds 3c and 3g exhibited the lowest IC₅₀ values (10.80 ± 0.14 and 11.62 ± 3.72 μM) against HuH-7 cells. Further investigations suggested compound 3c and 3g induced cell apoptosis, stimulated DNA damage, and autophagy against HuH-7 cells. Acute toxicity measurement also demonstrated the safety of the compounds. These findings suggested the triazole-cored analogs 3c and 3g are suggested to be promising candidates for the treatment of HCC and their potential for further pharmaceutical development.