Exploring Schiff Bases Derived from 2-hydroxybenzaldehyde as Potential Anticancer Agents: Synthesis,...

Chemotherapy resistance is a major obstacle in cancer; thus, the development of new anticancer agents is being studied with great importance. Schiff bases containing an azomethine group have been widely used in various pharmaceutical applications. Here, five Schiff base derivatives of 2-hydroxybenzaldehyde (8S1-8S5) were synthesized and characterized. Their cytotoxicity was screened against six cancerous and two normal cell lines using a neutral red uptake assay. The apoptotic mechanism of the compound 8S3 in MCF-7 cells was evaluated through a combination of cell cycle analysis, measurement of mitochondrial membrane potential, reactive oxygen species levels, caspase activity, analysis of gene expression in the mitogen-activated protein kinase (MAPK) signalling pathway, and in silico analysis studies. Treatment of the cells with 8S3 resulted in an increase in sub-G0/G1 populations and MMP disruption. The expressions of 30 genes involved in MAPK signalling were upregulated, while 10 genes were downregulated in these cells. This transcriptional profile supports a MAPK-mediated apoptotic response and highlights 8S3's potential to overcome chemoresistance by disrupting key survival MAPK signalling pathways. 8S3 might induces apoptosis through a mechanism involving modulation of MAPK pathway and mitochondrial dysfunction, in a ROS-independent manner. Results highlight 8S3's potential as a candidate for further development of anti-cancer drugs in cancer therapy.