Molecular Engineering of Cordycepin Derivatives for Enhanced Biological Activity and Stability

To address the metabolic instability of cordycepin induced by adenosine deaminase (ADA) and to enhance its bioactivity, this study developed eleven novel cordycepin derivatives using molecular engineering techniques. By incorporating sterically hindered protective groups and modifying the glycosyl moiety, the research aimed to improve both stability and efficacy. Antibacterial tests revealed that five derivatives showed significantly greater activity against pathogenic strains compared to cordycepin, with better compatibility with probiotics. Compound 2c demonstrated moderate antitumor activity against K562 and MGC‐803 cells, with IC50 values of 42.21 μM and 27.79 μM, respectively. Additionally, compound 4b demonstrated notable DPPH free radical scavenging ability. These compounds also showed improved stability in ADA solutions, providing valuable insights into the structure‐activity relationships of cordycepin derivatives.