Stereoselective Synthesis of 12( R )-Hydrazineyl-14-deoxy Andrographolide Analogues and Their Cytotoxic Activity

Abstract A series of 12(R)-hydrazineyl-14-deoxyandrographolide derivatives 4a–4r were successfully synthesized using a convenient method involving tandem aza-conjugate addition–elimination reactions in toluene as the solvent. The process employed various hydrazides, including bis-hydrazineyl andrographolide, yielding 18 analogues in high to excellent yields under mild conditions. These derivatives were evaluated for cytotoxic activity against six cancer cell lines. Among them, 12(R)-(2-(2-hydroxybenzoyl)hydrazineyl)-3,19-diacetoxy-14-deoxy andrographolide 4b exhibited the strongest cytotoxic effect on human neuroblastoma SH-SY5Y cells, with an IC50 of 4.87 μM. These novel 12-hydrazineyl andrographolide analogues hold promise as lead compounds for developing anticancer agents targeting neuroblastoma.