Design and synthesis of novel celastrol derivative and its antitumor activity in hepatoma cells and antiangiogenic activity in zebrafish

Wang, Gang; Xiao, Qin; Wu, Yao; Wei, Yingjie; Yue, Jing; Cao, Xiangrong; Gong, Zhaohui

doi:10.1002/jcp.28312

Cited by 18 publications

(8 citation statements)

References 71 publications

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“…Almost all the C-20 amide derivatives except for 4l showed equivalent or improved activities to at least one of the three cell lines. In particular, the antiproliferation effect of 4a , 4d , 4g , 4j, and 4m was higher than celastrol in all the screened cell lines.We speculated that the C-29 carboxyl group contributed finitely to the celastrol’s anti-tumour activity, consistent with previous studies’ conclusions 23 , 24 . Thus, the structural modification of E-ring for derivatives with enhanced activity worth further investigation.…”

Section: Resultssupporting

confidence: 91%

Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition

Fan

Wang

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Using STAT3 inhibitors as a potential strategy in cancer therapy have attracted much attention. Recently, celastrol has been reported that it could directly bind to and suppress the activity of STAT3 in the cardiac dysfunction model. To explore more effective STAT3 inhibiting anti-tumour drug candidates, we synthesised a series of celastrol derivatives and biologically evaluated them with several human cancer cell lines. The western blotting analysis showed that compound 4 m , the most active derivative, could suppress the STAT3’s phosphorylation as well as its downstream genes. SPR analysis, molecular docking and dynamics simulations’ results indicated that the 4m could bind with STAT3 protein more tightly than celastrol. Then we found that the 4m could block cell-cycle and induce apoptosis on HCT-116 cells. Furthermore, the anti-tumour effect of 4m was verified on colorectal cancer organoid. This is the first research that discovered effective STAT3 inhibitors as potent anti-tumour agents from celastrol derivatives.

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Section: Resultssupporting

confidence: 91%

Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition

Fan

Wang

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Normal-developed zebrafish embryos at 6hpf were selected under a microscope and fed in a 24‐well plate, with six eggs per well. 43 The exposure concentrations of celastrol were 0.1, 0.2, 0.5, 1, and 2 μM. The exposure concentrations of compound 2 were 0.1, 0.15, 0.2, 0.3, and 0.5 μM.…”

Section: Methodsmentioning

confidence: 91%

Synthesis and anticancer properties of celastrol derivatives involved in the inhibition of VEGF

Song,

Wen,

Hua

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this study, fourteen celastrol derivatives ( 1–14 ) were synthesised by esterification of celastrol at the 29th position. The in vitro anticancer activity of them was determined by the MTT assay. All the synthetic compounds showed significant antiproliferative activity against six cancer cells, with IC 50 of the submicron molar level. The most promising compound ( 2) blocked the cell cycle in the G2 phase and inhibited the expression of VEGF and MMP-9 in gastric cancer cell line MGC-803. In flow cytometry analysis, compound 2 induced cancer cell apoptosis in a dose-dependent manner. In the mouse tumour xenograft model, compound 2 showed significant anti-tumour activity in vivo at the dosage of 2.5 mg/kg and 1 mg/kg, with a higher inhibition rate than 5-FU (10 mg/kg). What’s more, the anticancer mechanism involved in the inhibition of VEGF and the toxicity evaluation of compound 2 were also investigated.

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“…Sample preparation was based on previous reports that employed the extraction of celastrol from biological samples with an organic solvent, subsequent evaporation of the supernatant to dryness, and the reconstitution of the residue in the mobile phase for the analysis (Guo et al, 2017;Huang et al, 2012;Wang et al, 2008Wang et al, , 2019Xu et al, 2007;Yan et al, 2017;Zhang et al, 2012). However, the extraction of celastrol from biological samples involves particular challenges due to its low solubility and chemical reactivity.…”

Section: Methods Developmentmentioning

confidence: 99%

Detection and quantification of the anti-obesity drug celastrol in murine liver and brain

Angelis

Schriever²,

Kyriakou

et al. 2020

Neurochemistry International

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Celastrol is a natural pentacyclic triterpene extracted from the roots of Tripterygium wilfordi (thunder god vine). Celastrol was reported as a powerful anti-obese drug with leptin sensitizing properties that decreases food consumption and mediates body weight loss when administered to diet-induced obese mice at 100 μg/kg body weight. The weight lowering properties of celastrol are likely mediated by the CNS, in particular, by the hypothalamus, but the final proof for the accumulation of celastrol in the brain and hypothalamus remains to be established. Here, we aimed to demonstrate that intraperitoneal celastrol administration at 100 μg/kg can rapidly reach the brain and, in particular, the hypothalamus of mice. We developed and validated a sensitive liquid chromatography mass spectrometry method for the quantitative determination of celastrol in murine tissues, namely liver, brain and hypothalamus. Chow-fed lean mice were randomly assigned to the vehicle vs. celastrol groups, injected with saline or 100 μg/kg body weight of celastrol, and sacrificed 30 min or 120 min post injection. Celastrol was extracted from homogenized tissue using ethyl acetate as organic solvent, and quantified using a matrix-matched calibration curve with glycyrrhetinic acid as internal standard. Liver celastrol concentrations were 32.60 ± 8.21 pg/mg and 40.52 ± 15.6 pg/mg, 30 and 120 min after injection, respectively. We found 4.70 ± 0.31 pg/mg celastrol after 30 min, and 16.22 ± 3.33 pg/mg after 120 min in whole brain lysates, and detectable amounts in the hypothalamus. These results corroborate the validity of our methodology, demonstrate the accumulation of celastrol in the brain of mice injected intraperitoneally with a dose of 100 μg/kg, and confirm the CNS as possible site of action for the weight lowering properties of celastrol.

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Design and synthesis of novel celastrol derivative and its antitumor activity in hepatoma cells and antiangiogenic activity in zebrafish

Cited by 18 publications

References 71 publications

Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition

Synthesis and biological evaluation of celastrol derivatives as potent antitumor agents with STAT3 inhibition

Synthesis and anticancer properties of celastrol derivatives involved in the inhibition of VEGF

Detection and quantification of the anti-obesity drug celastrol in murine liver and brain

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