Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma

Hepatocellular carcinoma is one of the most common primary hepatic malignancy. Herein, a series of semisynthesized derivatives ( 2 – 30 ) of the natural product (+)-sclerotiorin ( 1 ) was prepared and evaluated the cytotoxic activities against six cancer cell lines. Among them, 3 and 5 were the most effective compounds against human hepatocellular carcinoma Bel-7402 cell line with IC 50 values of 1.45 and 1.15 μ M, respectively. Molecular mechanism study showed that 5 disrupted the mitochondrial membrane potential and induced apoptosis in a caspase-dependent manner. In addition, 5 affected AKT and ERK signaling pathways and induced AKT and ERK proteins degradation through ubiquitin-proteasome system. Furthermore, 5 displayed significant in vivo anticancer effects in the xenograft models with decreasing the tumor mass by 52.5%. The safety evaluation was confirmed by acute toxicity subchronic toxicity tests, paraffin sections of mice organ and blood routine examination. Taken together, 5 can be developed as a potential therapeutic agent for hepatocellular carcinoma. • New (+)-sclerotiorin derivatives were semisynthesized and evaluated cytotoxic activities against six cancer cell lines. • Compound 5 induced AKT and ERK proteins degradation through ubiquitin-proteasome system. • Compound 5 decreased 52.5% of tumor weight in Bel-7402 xenograft tumor models without toxicity.