Design, Synthesis, and Evaluation of Cordycepin Derivatives as Antitumor Agents

ABSTRACT This study aimed to design and synthesize a series of novel cordycepin derivatives featuring urea groups to explore the antitumor efficacy of natural product derivatives with enhanced potency. The structures of the target compounds were characterized using infrared spectroscopy (IR), proton/carbon nuclear magnetic resonance spectroscopy ( 1 H and 13 C NMR), high‐performance liquid chromatography (HPLC), and high‐resolution mass spectrometry (HRMS). In vitro activity against MCF‐7, HepG‐2, SGC‐7901, and HK‐2 cells was evaluated using the standard methyl thiazolyltetrazolium assay (MTT), revealing that compound 4l exhibited significant inhibitory effects on HepG‐2 cells (IC 50 = 14.86 ± 2.37 µM), outperforming cordycepin. Mechanistic studies indicated that 4l induced dose‐dependent apoptosis, arrested the cell cycle at the G 0 /G 1 phase, and activated the intrinsic mitochondrial pathway. Molecular docking simulations further elucidated its binding mode with target proteins. Collectively, compound 4l shows promise as a candidate drug for liver cancer therapy.