Design and synthesis of guaianolide‐germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma.

Inspired by our previous finding that disesquiterpenoids showed more potent antihepatoma cytotoxicity than their corresponding parent monomers, natural product‐like guaianolide‐germacranolide heterodimers were designed and synthesized from guaianolide diene and germacranolides via a biomimetic Diels–Alder reaction to provide three antihepatoma active dimers with novel scaffolds. To explore the structure–activity relationship, 31 derivatives containing ester, carbamate, ether, urea, amide, and triazole functional groups at C‐14′ were synthesized and evaluated for their cytotoxic activities against HepG2, Huh7, and SK‐Hep‐1 cell lines. Among them, 25 compounds were more potent than sorafenib against HepG2 cells, 15 compounds were stronger than sorafenib against Huh7 cells, and 17 compounds were stronger than sorafenib against SK‐Hep‐1 cells. Compound 23 showed the most potent cytotoxicity against three hepatoma cell lines with IC50 values of 4.4 µM (HepG2), 3.7 µM (Huh7), and 3.1 µM (SK‐Hep‐1), which were 2.7‐, 2.2‐, and 2.8‐fold more potent than sorafenib, respectively. The underlying mechanism study demonstrated that compound 23 could induce cell apoptosis, prevent cell migration and invasion, cause G2/M phase arrest in SK‐Hep‐1 cells. Network pharmacology analyses predicted PDGFRA was one of the potential targets of compound 23, and surface plasmon resonance (SPR) assay verified that 23 had strong affinity with PDGFRA with a dissociatin constant (KD) value of 90.2 nM. These promising findings revealed that structurally novel guaianolide‐germacranolide heterodimers might provide a new inspiration for the discovery of antihepatoma agents. [ABSTRACT FROM AUTHOR]