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

Abstract

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, <b>10b</b>, exhibited potent activity against the HepG-2 cell line with an IC₅₀ value of 0.63 μM. Moreover, compound <b>10b</b> 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 <b>10b</b> indicated that <b>10b</b> could inhibit P-STAT3 to induce the activation of mitochondrial apoptotic pathways. An in vivo acute toxicity study indicated that the compound <b>10b</b> has preferable safety and tolerability compared with cucurbitacin B. These findings indicate that compound <b>10b</b> might be considered as a lead compound for exploring effective anti-HCC drugs.