Structure-guided optimization of N-sulfonylpiperidines toward potent multi-target anticancer agents

Cancer poses a significant therapeutic challenge due to its multifactorial origin and resistance to conventional remedies. Our previous efforts identified N-sulfonylpiperidine derivatives as potent VEGFR-2 inhibitors (Compound A). Herein, we report a rational design, synthesis, and biological assessment of a new series of analogs to enhance anticancer efficacy through scaffold optimization and multi-target engagement. Strategic modifications on A included group repositioning, diversifying the terminal aromatic substituents, and linker replacement. Among the synthesized derivatives, compound 16 exhibited promising cytotoxic activities across three cell lines, in comparison with the lead compound A and vinblastine. Preliminary mechanistic studies confirmed that 16 induced G0/G1 cell cycle arrest and promoted early apoptosis in MCF-7 cells. Enzyme inhibition assays further revealed that our derivative acts as a dual inhibitor of VEGFR-2 and EGFR versus moderate activity against topoisomerase II. Molecular docking studies supported these findings by showing favorable binding orientations and interactions within the VEGFR-2 active site. The binding pattern of 16 showed key hydrogen bonding and hydrophobic contacts that enhance ligand affinity. Altogether, this work highlights the impact of these modifications and introduces 16 as a promising lead to develop multitargeted anticancer therapeutics that inhibit tyrosine kinases and DNA-processing enzymes.