Design, Synthesis and Biological Evaluation of Aminoalkylated Paeonol Chalcone Derivatives

Twenty-six novel derivatives of paeonol chalcone were synthesized by introducing various hydrophilic aminoalkyl to the 2'-hydroxy of paeonol. Their antiproliferative activity was evaluated by MTT assay against five human cancer cell lines (HeLa, HepG2, U2OS, HCT-116 and A549). The majority of these compounds demonstrated remarkable cytotoxicity against the tested cancer cells. Among them, compound 4k exhibited the most potent antiproliferative activity (IC₅₀ values ranging from 1.31 μM to 7.56 μM for the tested cancer cells), stronger than 5-FU (IC₅₀ = 6.29-14.56 μM). Notably, it effectively inhibited the proliferation of HeLa/Taxol cells (IC₅₀ = 14.47 ± 0.02 μM) while showing low cytotoxicity toward normal liver epithelial THLE-2 cells (IC₅₀ = 26.40 ± 0.04 μM). Preliminary mechanistic studies revealed that compound 4k induces apoptosis in HeLa cells and downregulates the expression of Cyclin B1 and CDK1, leading to cell cycle arrest at the G2/M transition. Solubility studies revealed that 5k (4k hydrochloride) showed excellent aqueous solubility (11.53 mg/mL). SwissADME predictions further supported its potential druggability. Collectively, compound 4k represents a promising lead worthy of further investigation as a potential antitumor agent.