Design, synthesis, in silico, in vitro and in vivo anticancer potential of sulphonamide- ethylamine-triazole-aryl in against triple negative breast cancer and Dalton lymphoma.

Abstract

This study aimed to synthesize a novel series of sulphonamide-ethylamine-triazole-aryl derivatives as potential anticancer agents. The compounds were synthesized using an efficient click reaction and characterized by 1H, 13C NMR, HRMS and HPLC. Anticancer potential was tested against human breast cancer SK-BR-3, MDA-MB-231 and MCF-7, along with cervical cancer HeLa and non-oncogenic HEK-293 cells. Among the synthesized derivatives (4a-4o), compound 4c showed the most significant apoptotic activity in MDA-MB-231 cells, with an IC50 of 15μM, while exhibiting minimal toxicity towards non-oncogenic HEK-293 cells. Mechanistic studies revealed that 4c markedly increased intracellular ROS levels, mitochondrial dysfunction (Mito-tracker and JC-1 assay), which may lead to mitochondrial-mediated apoptosis. This was confirmed by AO/EtBr dual staining, which showed characteristic apoptotic features such as chromatin condensation and membrane blebbing, which was again validated through Annexin/V and Caspase-3/7 assay. Flow cytometric cell-cycle analysis further demonstrated that 4c induced G2/M phase arrest, a critical checkpoint dysregulation that may also contribute to its pro-apoptotic effects. In vivo studies showed strong antitumor efficacy of 4c in Dalton lymphoma, comparable to docetaxel, while suppressing tumor progression with reduced toxicity. Molecular docking studies also identified compounds 4a, 4c, 4 h, and 4 m as promising binders towards tyrosine-protein kinase. ADMET and drug-likeness analysis of compounds 4a-4o supported the favourable profile of 4c. Overall, these findings suggest that 4c exerts anticancer activity through ROS-mediated mitochondrial apoptosis and cell-cycle disruption, highlighting its promise as an oncotherapeutic candidate for TNBC and Dalton lymphoma.