Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation

Hill, Timothy A.; Stewart, Scott G.; Ackland, Stephen P.; Gilbert, Jayne; Sauer, Benjamin; Sakoff, Jennette A.; McCluskey, Adam

doi:10.1016/j.bmc.2007.06.034

Cited by 88 publications

(81 citation statements)

References 14 publications

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“…11 It has become a kind of widely used antitumor drug with China's independent intellectual property rights. [12][13][14] Our previous study found that it has an anti-tubulointerstitial fibrosis function in protein overload nephropathy models 4 and obstructive nephropathy models (data not shown). This study was designed to observe the effect of NCTD on renal fibrosis in DN nephropathy.…”

Section: Discussionmentioning

confidence: 86%

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Chen

Liu

et al. 2011

Renal Failure

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Objective: To investigate the effects of norcantharidin (NCTD) on tubulointerstitial fibrosis of diabetic nephropathy (DN) in streptozotocin-induced rat model. Methods: Sprague-Dawley rats were randomly divided into control group, model group, low-dose NCTD (0.05 mg/kg/day) group, and high-dose NCTD (0.1 mg/kg/day) group. The model group was induced by injection intraperitoneally with 30 mg/kg streptozotocin in 0.1 mol/L sodium citrate solution (pH 4.5), after high-calorie foods were given for 2 months. NCTD was administered daily after the DN rat model was built. Rats were sacrificed at the end of the third and the eighth week; renal fibrosis and the expression of FN, collagen IV, TGF-b1, and calcineurin (CaN) were detected by Masson and immunohistochemistry staining, respectively. Results: Tubulointerstitial fibrosis was observed in DN rats, this kind of pathological changes was ameliorated in NCTD treatment group (p < 0.05). The expressions of FN, collagen IV, and TGF-b1 protein increased in the tubulointerstitial field of DN rats compared with the rats in control group. NCTD treatment could dose-dependently decrease their expression and reverse the fibrotic degree (p < 0.05). Meanwhile, the expression of CaN was detected in tubular fields of normal kidney and increased in the tubulointerstitial field in DN rats. However, NCTD downregulated its expression in a dosedependent manner (p < 0.05). Conclusions: NCTD could downregulate FN, collagen IV, and TGF-b1 expression in tubulointerstitial fields and attenuate tubulointerstitial fibrosis in the early stage of DN rats. NCTD also alleviated the expression of CaN in tubules in DN. The relationship between the role of NCTD's anti-tubulointerstitial fibrosis and its inhibition to CaN expression remains to be further elucidated.

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Section: Discussionmentioning

confidence: 86%

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Chen

Liu

et al. 2011

Renal Failure

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“…DISCUSSION NCTD, a synthesized demethylated form of cantharidin and an active ingredient of the Chinese medicine Mylabris, is now in wide use as a routing anticancer drug against digestive tract cancer. 14,15 With few side effects, NCTD is also regarded as an attractive potential therapeutic agent in cancer chemotherapy in Western countries. 4 It has been demonstrated that the mechanisms by which NCTD inhibits the growth of malignant cells correlate with the blockade of DNA synthesis, arrest of the cell cycle, and induction of P53-and Bcl-2-dependent apoptotic pathways.…”

Section: Effects Of Nctd On Can/nfatc Signaling Pathway In Hk-2 Cellsmentioning

confidence: 99%

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

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Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-b1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-b1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (Po0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-b1 of HK-2 cells stimulated by high glucose (Po0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (Po0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-b1 increased in HK-2 cells stimulated by high glucose (Po0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-b1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-b1 was not associated with its inhibition of the CaN/NFAT pathway.

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“…Lastly, to enhance its anticancer activity, various structural modifications of norcantharidin had been studied and mixed results had been reported. For instance, an analog of norcantharidin was shown to inhibit the function of protein phosphatase and had anti-proliferative activity while others bioactivities were erased [33][34][35][36][37][38][39]. In the previous study, it has been reported that norcantharimide analogues bearing a long alkyl chain at N-position may have enhanced bioavailability and transportability through cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Lipophilic N-Substituted Norcantharimide Derivatives and Evaluation of Their Anticancer Activities

Kuo

Chu

et al. 2014

Molecules

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This research attempted to study the effect of lipophilicity on the anticancer activity of N-substituted norcantharimide derivatives. Twenty-three compounds were synthesized and their cytotoxicities against five human cancer cell lines studied. The lipophilicity of each derivative was altered by its substituent, an alkyl, alkyloxy, terpenyl or terpenyloxy group at the N-position of norcantharimide. Further, among all synthesized derivatives studied, the compounds N-farnesyloxy-7-oxabicyclo[2.2.1]heptane-2, 3-dicarboximide (9), and N-farnesyl-7-oxabicyclo[2.2.1]heptane-2,3-dicarboximide (18), have shown the highest cytotoxicity, anti-proliferative and apoptotic effect against human liver carcinoma HepG2 cell lines, yet displayed no significant cytotoxic effect on normal murine embryonic liver BNL CL.2 cells. Their overall performance led us to believe that these two compounds might be potential candidates for anticancer drugs development.

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Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation

Cited by 88 publications

References 14 publications

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Norcantharidin Attenuates Tubulointerstitial Fibrosis in Rat Models with Diabetic Nephropathy

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Synthesis of Novel Lipophilic N-Substituted Norcantharimide Derivatives and Evaluation of Their Anticancer Activities

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