Microwave-Assisted Synthesis, Cytotoxic Profile, and Cellular Mechanism Analysis of Carveoylphenol Derivatives.

A series of carveoylphenol derivatives (1-12) was synthesized using a microwave-assisted approach and evaluated through an integrated in vitro and in silico strategy. Cytotoxicity was assessed against PC-3, MCF-7, and HT-29 human cancer lines, using non-tumorigenic CoN CCD841 cells as a reference. Derivatives 1, 2, 5, 6, 7, 8, and 11 exhibited activity (IC50 < 100 µM) against at least one cancer line, with 2 showing the highest potency (IC50 = 23.2 µM). Flow cytometry of compounds 1, 2, and 5 revealed structure-dependent cellular responses, where 2 at 40 µM induced maximum intracellular ROS generation (39.6%), 1 reduced mitochondrial membrane integrity to 42.1% intact cells, and 5 produced peak caspase activation (34.5%). Molecular docking against caspase-3 yielded predicted binding energies for all three molecules, with 5 scoring -6.4 kcal/mol. SwissADME analysis indicated comparable physicochemical profiles, high predicted gastrointestinal absorption, and potential blood-brain barrier permeability for these three derivatives. Overall, carveoylphenols, particularly compound 2, represent promising scaffolds for further structural optimization and mechanistic investigation.