Synthesis, Cytotoxicity, and Quantitative Structure–Activity Relationship Studies of Alkyl Triphenylphosphonium Pinostrobin Derivatives

Abstract Pinostrobin, an isolated compound from Boesenbergia rotunda , has been shown to have potent anti‐proliferation and apoptosis effects in cancer stem‐like cells. However, its hydrophobic properties reduce its bioavailability. Eight new alkyl‐TPP + pinostrobin derivatives were synthesized and assessed for their cytotoxicity against the human HepG2 liver cancer cell line using the alamarBlue assay. All derivatives exhibited moderate cytotoxicity, with the IC 50 values ranging from 38.55–101.95 μ M, and were more potent than pinostrobin and pinostrobin hydrazone (IC 50 >100 μ M). Four alkyl‐TPP + pinostrobin hydrazone amide derivatives showed more potent cytotoxicity than four alkyl‐TPP + pinostrobin ester derivatives. QSAR analysis showed key 3D structural descriptors of TPP + ‐based compounds responsible for cytotoxicity against HepG2 cells for the first time. The resultant 3D‐QSAR models using PLS and PCR methods were evaluated and found reliable in predicting the cytotoxicity of other TPP + ‐based compounds.