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.