The Potential Targets of Novel Triazine Derivatives on Mechanisms of Apoptosis, Regulation of the Cell Cycle, and Endoplasmic Reticulum Stress Pathways in Human Lung Cancer

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ABSTRACT Understanding the complex connections between cellular mechanisms is crucial for developing effective cancer treatments. In this study, new Schiff base derivative triazine compounds ( 5–8 ) were synthesized and structurally characterized using various spectroscopic techniques to investigate their cellular and gene‐protein‐level effects in lung cancer and to develop anticancer activity strategies. The cytotoxic activities of compounds were evaluated against A549 and MRC‐5 cell lines using the WST‐8 assay. Moreover, cellular death mechanisms in lung cancer were investigated using methods such as qRT‐PCR, ELISA, membrane array, and Flow cytometry. In lung cancer cells, compounds 5 (58.24%) and 6 (59.08%) were mildly effective in terms of cell viability, and these two compounds exhibited cytotoxic activity at a dose of 50 µM. Also, while an increase in the expressions of the p21, p27, and p53 genes was observed across all compounds in A549 cells, a decrease in the expressions of the GRP78, GRP94, AKT, RIPK1, CDK1, CDK2, HSP27, HSP40, HSP60, and HSP90 genes was observed. Besides, GRP78 and Caspase‐3 were considerably increased by compounds 5 and 6 . While Caspase‐3, CHK1, P38, P53, and TRAILR‐2 pro‐apoptotic protein expressions increased, BCL‐2, BCL‐W, IGF‐II, and NF K B anti‐apoptotic protein expressions decreased for all compounds. The G0/G1 phase was increased by compounds 5 and 6 . Although these compounds attenuated both the S and G2/M phases. Overall, the new triazines target dysregulated cell‐cycle, ER stress, and apoptotic pathways, demonstrating strong therapeutic potential in lung cancer. Notably, compounds 5 and 6 exhibited cytotoxic and pathway‐modulating activities, highlighting their promise as clinically relevant lead candidates.