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

In Vitro and In Vivo Antitumor Activity of Cucurbitacin C, a Novel Natural Product From Cucumber

“…For instance, cucurbitacins B, D, E, and I are the most wildly studied variants and exhibit general in vitro and in vivo anti-cancer effects. Cucurbitacin B shows significant inhibition effects in breast cancer (Jin et al, 2018), liver cancer (Ge et al, 2018), and glioblastoma multiforme (Qin et al, 2018); cucurbitacin E exerts anti-cancer activities in treating brain cancer (Cheng et al, 2019) and gastric cancer (Jafargholizadeh et al, 2018); cucurbitacin D is effective to treat cervical cancer (Sikander et al, 2016) and breast cancer (Ku et al, 2015); and cucurbitacin I also processes anti-cancer activities (Kim and Kim, 2015; Wu et al, 2016; Ni et al, 2018). Moreover, cucurbitacins can also inhibit tumor angiogenesis (Touihri-Barakati et al, 2017; Piao et al, 2018), enhance anti-proliferative activity of chemotherapy drugs (Sadzuka et al, 2010; Aribi et al, 2013), and suppress cancer cell stemness (Shukla et al, 2016).…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Therefore, studies have been focused on tackling this side effect, and some cucurbitacin B derivatives have been synthesized to screen for effective cancer therapy with safety and tolerability. Compound 10b, one of the derivatives of cucurbitacin B, shows more potent anti-cancer activity than cucurbitacin B [496]. The in vivo acute toxicity study also shows that compound 10b has better tolerability and safety than cucurbitacin B.…”

HPMA-Based Copolymers Carrying STAT3 Inhibitor Cucurbitacin-D as Stimulus-Sensitive Nanomedicines for Oncotherapy

“…Moreover, diverse STAT3 inhibitors have already been shown to be effective by inducing the apoptosis of tumor cells [ 10 , 11 , 12 , 13 , 14 ]. Cucurbitacins are highly oxygenated tetracyclic triterpenes, which show potent pharmacological effects, including anticancer activity [ 15 , 16 , 17 , 18 , 19 , 20 ]. Moreover, the dose necessary for cucurbitacins to present a therapeutical effect is much lower than the toxic dose, thus increasing their potential as therapeutic agents [ 19 ].…”

“…Moreover, the dose necessary for cucurbitacins to present a therapeutical effect is much lower than the toxic dose, thus increasing their potential as therapeutic agents [ 19 ]. Among cucurbitacin derivatives, cucurbitacin-D (CuD) showed an effective inhibitory effect on the proliferation of colon, breast, lung, cervical, and prostate cancer cell lines as a result of Janus kinase/signal transducer activator of transcription 3 (JAK/STAT3) signaling pathway inhibition [ 15 , 16 , 18 , 19 , 20 ]. Studies also identified that the combination of cucurbitacins and anticancer agents can promote a synergism and may augment the chemotherapeutic effects via suppression of STAT3, being promising for tumor treatment [ 17 , 20 ].…”

“…However, there are significant limitations concerning the potential clinical application of cucurbitacins due to their poor water solubility [ 21 ], high toxicity, low selectivity, and narrow therapeutic window for treatment [ 15 , 17 ]. To overcome these limitations, polymeric carriers were designed for effective solubilization of cucurbitacins, controlled delivery, and sustained rate of release in cancerous tissue.…”