Novel sulfonamide-aromatic amine hybrids: Synthesis, cytotoxic screening, and transcriptomic insights into anticancer activity

Cancer remains one of the causes of mortality worldwide and a major global health challenge. These challenges are attributed to factors such as medication resistance, tumor complexity, and heterogeneity. Targeted therapy with small molecules has emerged as a promising approach due to its ability to selectively inhibit cancer cell growth while minimizing off-target effects. In this study, a series of derivatives synthesized from 3-formyl-4-hydroxy benzene sulfonyl chloride (FHS) were evaluated for their cytotoxic effects on various cancer cells. The objective was to identify compounds with potent anticancer activity and favorable selectivity profiles for further development. The synthesis process began with FHS as the starting material, subjected to a series of chemical reactions to generate a library of compounds labeled C3 through C10. These compounds were characterized by using a combination of analytical techniques, including melting point determination, Proton Nuclear Magnetic Resonance ( 1 H NMR), Carbon-13 Nuclear Magnetic Resonance ( 13 C NMR), and Infrared (IR) spectroscopy to confirm their structural integrity. Cytotoxic effects were evaluated using Sulforhodamine B (SRB) assay for cytotoxicity was applied to an extensive panel of cancer cell lines, categorized into such as colorectal cancer (HT-29, MC38, CT26and COLO 205), hepatic (C3a and PLC/PRF), pancreatic (Suit-2, MiaPaca2, As-PC1 and Panc 02.03, CI66), breast (MDA-MB-468, MDA-MB-231, BT20, MCF7, 4T1, 4T1 paclitaxel resistant, JIMT-1, ZR-75-1, E0771, T47D, and HCC1806) and ovarian (OVCAR-5) cell lines. Normal breast epithelial cell line MCF10a was tested to analyze safety. Based on the SRB assay, 7 compounds exhibited variable but significant cytotoxicity in various cancer models. The most effective compound, C5, was chosen for further analysis to identify mechanism of its cytotoxic effect by transcriptomic analysis. The transcriptomic results showed ten genes with log2 fold change between control and treatment. These genes were related to DNA damage inducible transcript 4, FXYD domain containing ion transport regulator 4 and CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1). Further in vivo experiments and validation experiments are in progress to determine the most significant pathway for cytotoxicity.