Design, Synthesis, and Biological Evaluation of Evodiamine Derivatives as Antibody–Drug Conjugate Payloads

Natural product evodiamine derivatives exhibit multitarget bioactivities as dual topoisomerase (TOPO) I/II inhibitors, demonstrating remarkable potential in antitumor applications. Based on the evodiamine derivative D7‐03, six derivatives are synthesized. In vitro screening shows that D7‐09 has the strongest antitumor activity (IC 50 = 9.75–26.11 n m ) but poor hydrophobicity and solubility. D7‐03 with nM‐level cytotoxicity, better physicochemical properties, and high yield is chosen as the core payload for antibody‐drug conjugate (ADC) construction. The active molecule D7‐03 is further explored as an ADC payload by constructing four linker–toxin complexes. These complexes are conjugated with trastuzumab to generate ADC candidate molecules. Notably, Ab‐DL07‐D7‐03 exhibits superior activity (IC 50 = 8.369 and 4.899 n m 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.