Structural Diversification of Fangchinoline via a CuAAC Reaction: Design, Batch and Semi‐Flow Synthesis, and Anticancer Activity Evaluation

ABSTRACT In this study, we reported late‐stage structural diversification of fangchinoline (FC) via a CuAAC method to incorporate multifunctional 1,2,3‐triazole scaffolds. A series of new C7‐substituted FC derivatives were designed, synthesized, and evaluated as anticancer agents. Considering the superior heat and mass transfer characteristics of flow chemistry, we also employed a practical modification strategy of FC with higher yields in a simple loop reactor. Notably, FC01 , FC03 , and FC05 exhibited high antitumor activities against HeLa, MCF‐7, and HCT‐116 cells, respectively. These three compounds demonstrated two to fourfold greater potency than the parent compounds tetrandrine and FC. Although 1,2,3‐triazole and carbamate were both recognized as amide bioisosteres, in contrast to FC derivatives bearing carbamate linkage on C7 position, the better anticancer activities of 1,2,3‐triazole‐containing compounds indicated that both the linkage and side chain provided major contributions to cytotoxicity activities. These results were further confirmed by molecular docking with protein kinase C‐α. In addition, pharmacological assays revealed that FC05 could inhibit proliferation and induce apoptosis, as well as arrest the cell cycle of HCT‐116 cell lines at G0/G1 phase arrest with concentration‐dependent effects.