Design, Synthesis, and Biological Evaluation of Evodiamine Derivatives as Antibody‐Drug Conjugate (ADC) Payloads

Natural product evodiamine derivatives exhibit multitarget bioactivities as dual TOPO I/II inhibitors, demonstrating remarkable potential in antitumor applications. Based on the evodiamine derivative D7‐03, six derivatives were synthesized. In vitro screening showed that D7‐09 had the strongest anti‐tumor activity (IC50 = 9.75‐26.11 nM) but poor hydrophobicity and solubility. D7‐03, with nM‐level cytotoxicity, better physicochemical properties, and high yield, was chosen as the core payload for ADC construction. The active molecule D7‐03 was further explored as an antibody‐drug conjugate (ADC) payload by constructing four linker‐toxin complexes. These complexes were conjugated with trastuzumab to generate ADC candidate molecules. Notably, Ab‐DL07‐D7‐03 exhibited superior activity (IC50 = 8.369 nM and 4.899 nM in HCC1954 and NCI‐N87 cells, respectively) compared to the control group Ab‐LC08‐SN38. This study is the first application of evodiamine derivatives as TOPO I / II dual inhibitors in the ADC field, which not only provides a new strategy for the development of ADC payloads but also enriches the innovative application of natural product small molecules in tumor‐targeted therapy.