Novel hybrid salicylaldehyde-sulfonamide schiff bases elicit an ISR-associated transcriptomic response and suppress cancer cell survival.

In this study, we describe the rational design, synthesis, and biological evaluation of a novel series of salicylaldehyde-derived sulfonamide Schiff base hybrids. Eight compounds (C3-C10) were synthesized via condensation of 3-formyl-4-hydroxybenzenesulfonyl chloride with diverse primary amines and extensively characterized using IR, NMR, and MS/MS. Synthesized compounds were evaluated for their cytotoxicity in a variety of pancreatic, breast, colorectal, hepatic and ovarian cancer cell lines, and compound C5 was identified as the lead candidate, with an IC₅₀ ranging 4.1-75 μM across the complete cancer-cell panel. Interestingly, C5 exhibited lower cytotoxicity towards the normal nonmalignant cells as compared to cancer cell lines indicating selectivity. Transcriptomic profiling (RNA-seq) in SUIT-2 pancreatic cancer cells treated with C5 identified a gene expression signature that was associated with the activation of integrated stress response (ISR) through upregulation of key stress-associated genes, alongside suppression of oncogenes. Gene ontology and pathway enrichment analysis demonstrated significant modulation of ER stress, unfolded protein response, amino acid metabolism, and lipid metabolic pathways, indicating metabolic reprogramming and stress adaptation. Long non-coding RNA (lncRNA) profiling identified treatment-associated changes in stress- and cancer-related transcripts. Taken together, these findings identify C5 as a promising lead compound with anticancer activity associated with modulation of cellular stress-response pathways and metabolic pathways.