Discovery of β-cyclocitral-derived mono-carbonyl curcumin analogs as anti-hepatocellular carcinoma agents via suppression of MAPK signaling pathway

[Display omitted] •A series of β-cyclocitral-derived mono-carbonyl curcumin analogs are synthesized.•A19 significantly inhibits cell proliferation and induces cell apoptosis.•A19 inhibits DNA synthesis of HCC cells and triggers intense DNA damage.•A19 suppresses the ERK/JNK/p38 MAPK signaling pathway in HCC cells.•A19 synergizes with sorafenib in HCC cells in vitro. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high recurrence and mortality rate. In this study, a series of β-cyclocitral-derived mono-carbonyl curcumin analogs were synthesized and their anticancer properties were evaluated. Among the series, A19 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest and cell apoptosis of HCC HepG2 and Huh-7 cells, while having almost no cytotoxicity on normal liver MIHA cells. Mechanistically, our results demonstrated that A19 triggered intense DNA damage via suppression of the ERK/JNK/p38 MAPK signaling pathway. Additionally, a combination of A19 with sorafenib significantly induced synergistic cytotoxicity in HCC cells. Overall, our results indicate the potential of A19 as a novel chemotherapeutic drug administered either separately or in combined therapy for HCC treatment.