Novel agents derived from natural product β-elemene: A second round of design and synthesis to enhance antitumor properties.

Natural products play a key role in drug discovery and development. The natural sesquiterpene, β-elemene, has been approved as an antitumor drug in China. Despite showing few side effects, the moderate antitumor potency of β-elemene hampers its wide application in clinic. A second round of design and synthesis of β-elemene derivatives was carried out based on our previous prodrug-like ester derivatives. The resulting twenty-nine compounds (except 10c) exhibited enhanced antitumor activity compared with β-elemene and its ester derivative 3. The optimal compound 10a possessed low micromolar antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and U87), more potent than positive control cisplatin. The mechanism studies indicate that compound 10a caused arrest of the cell cycle along with inhibition of microtubules, induced apoptosis via a ROS-involved mitochondrial apoptotic pathway, and dampened cell migration and invasion with changes of related protein (MMP-9 and p-FAK) expressions. Collectively, the promising antitumor efficacy of compound 10a would make it a potential lead compound in anticancer drug development.