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 (IC₅₀ = 9.75-26.11 nm) 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 (IC₅₀ = 8.369 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.