Synthesis, Structure–Activity Relationship, and Biological Evaluation of a Novel Malabaricone Derivative: A Potent Anticancer Agent and Radiosensitizer That Targets Autophagy Flux

Polyphenolic malabaricones, from edible spice (Rampatri, Myristica malabarica), show potent anticancer properties against multiple cancers. Malabaricones typically contain diarylnonanoid as a core moiety with different functional groups. Currently, the association of the specific chemical structure of malabaricones with their anticancer activities is not yet known. In the present study, a novel series of 19 analogues of malabaricone C were designed, synthesized, and evaluated for their structure–activity relationship for the first time. For synthesis, various phenyl β-ketoesters were reacted with ω-aryl alkyl bromides/alkyl bromides, followed by decarboxylation of the ester moiety. The antiproliferative potential of all analogues was systematically evaluated through MTT and clonogenic assays using human breast adenocarcinoma cells. Among the analogues, malabaricone analogue (ML-20), lacking a carbonyl functionality, exhibited impressive threefold higher antiproliferative effects than naturally available potent malabaricone C. In addition to reducing clonogenic cell survival, ML-20 increased the sub-G1 cell population and annexin-V-stained cells in a dose-dependent manner, indicating the activation of apoptosis. Mechanistically, ML-20 induces robust DNA double-strand breaks, loss of mitochondrial membrane potential (MMP), and lysosomal membrane permeabilization (LMP) in breast cancer cells. Our study also demonstrated that owing to its ability to induce endoplasmic reticulum stress and concurrent inhibition of autophagy flux due to LMP, ML-20 could serve as a potential autophagy inhibitor and radiosensitizer. Above results manifested lead compound ML-20 as a potent malabaricone analogue, which may be used as a potential adjuvant for cancer therapy.