Synthesis of Cucurbitacin B Derivatives as Potential Anti-Hepatocellular Carcinoma Agents.

Cucurbitacin B shows potent activity against tumor cells, but its high toxicity limits its application in the clinic. A series of cucurbitacin B derivatives was synthesized and evaluated for their anti-hepatocellular carcinoma (HCC) activities against the HepG-2 cell line. These compounds were also tested for their toxicity against the L-O2 normal cell line. The compound with the most potential, , exhibited potent activity against the HepG-2 cell line with an IC value of 0.63 μM. Moreover, compound showed the highest TI value (4.71), which is a 14.7-fold improvement compared to its parent compound cucurbitacin B. A preliminary molecular mechanism study of indicated that could inhibit P-STAT3 to induce the activation of mitochondrial apoptotic pathways. An in vivo acute toxicity study indicated that the compound has preferable safety and tolerability compared with cucurbitacin B. These findings indicate that compound might be considered as a lead compound for exploring effective anti-HCC drugs.