Microbial transformation of three bufadienolides by Nocardia sp. and some insight for the cytotoxic structure–activity relationship (SAR)

Zhang, Jian; Sun, Yang; Liu, Jihua; Yu, Boyang; Xu, Qiang

doi:10.1016/j.bmcl.2007.09.065

Cited by 36 publications

(11 citation statements)

References 30 publications

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“…After analyzing and comparing these data online (SciFinder Scholar) with reported compounds and references, the structures of Compounds 1 and 2 were identified as resibufogenin (Compound 1) and cinobufagin (Compound 2) (Fig. 1), which were previously detected in the parotid secretions of the toads B. marinus, B. gargarizans and B. melanostictus (15,16).…”

Section: Identification Of the Active Compounds Compound 1 Was Obtaimentioning

confidence: 99%

Apoptosis-inducing activity of compounds screened and characterized from cinobufacini by bioassay-guided isolation

Wang

Qi²,

Xu³

et al. 2010

Mol Med Rep

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Abstract. cinobufacini (huachansu), an aqueous extract from the skin of the toad Bufo bufo gargarizans cantor, is a traditional chinese medicinal preparation widely used in clinical cancer therapy in China. Here, we screened and identified active compounds of cinobufacini and investigated their apoptosisinducing effect on HepG 2 cells. Screening was performed using bioassay-guided isolation. The effects of different fractions on the proliferation of HepG 2 cells were detected by the MTT assay. The extraction and isolation of active fractions were performed by chloroform extraction, silica column chromatography, preparative thin-layer chromatography and high-performance liquid chromatography. Nuclear magnetic resonance (NMR) imaging and electron ionization-mass spectrometry (EI-MS) were used to identify the structure of the active compounds. The extent of cell apoptosis was detected by Hoechst 33258 staining and flow cytometric analysis. Western blot analysis was used to detect the expression of the apoptosis-related proteins Bax and Bcl-2. Through bioassay-guided isolation, two compounds were isolated from cinobufacini. nMr and ei-MS data revealed these compounds to be resibufogenin and cinobufagin. Cinobufagin was determined to be the more efficient of the two in inhibiting the proliferation of HepG 2 cells. Hoechst 33258 staining and flow cytometric analysis indicated that cinobufagin induced marked changes in apoptotic morphology and significantly increased the proportion of apoptotic cells in HepG 2 cells. Western blot analysis showed that cinobufagin up-regulated Bax expression and down-regulated Bcl-2 expression. In conclusion, we screened and identified two anti-proliferation compounds of cinibufacini, resibufogenin and cinobufagin. The most effective compound, cinobufagin, inhibited cell proliferation by inducing the apoptosis of HepG 2 cells. This was potentially triggered by regulation of the Bax/ Bcl-2 ratio.

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Section: Identification Of the Active Compounds Compound 1 Was Obtaimentioning

confidence: 99%

Apoptosis-inducing activity of compounds screened and characterized from cinobufacini by bioassay-guided isolation

Wang

Qi²,

Xu³

et al. 2010

Mol Med Rep

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“…[12] Bufadienolides, such as, bufotalin, bufalin, cinobufagin, and resibufogenin, have been reported as Na + -K + -ATPase inhibitors and exhibit cytotoxic and growth-inhibitory activity against various human cancer cells in vitro . [1314]…”

Section: Introductionmentioning

confidence: 99%

Comparison of toad skins Bufo bufo gargarizans Cantor from different regions for their active constituents content and cytotoxic activity on lung carcinoma cell lines

et al. 2014

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Background:The skin of Bufo bufo gargarizans Cantor, rich in bufadienolides, peptides, and alkaloids, has approved pharmacological activity for preliminary anti-liver and lung tumor treatment. However, few studies have systematically focused on the influence of the producing regions on the content and antitumor activity of the active constituents in toad skins.Objective:This study aims to compare toad skins obtained from six different regions in China (Jiangsu, Anhui, Henan, Hebei, Jiangxi, and Shandong province) for their bufadienolide and alkaloid content, and their cytotoxic activity on two lung carcinoma cell lines (SPC-A-1 cells and A549 cells).Materials and Methods:High performance liquid chromatography (HPLC) was used to quantificationally determine four bufadienolides, which included bufotalin, bufalin, cinobufagin, and resibufogenin in toad skins, from six different regions, respectively. In addition, an ultraviolet (UV) spectrophotometer was also employed to identify the content of the total alkaloids using 5-hydroxytryptamine (5-HT) as the reference substance. An MTT assay was performed to compare the antiproliferative effects of the toad skins’ ethanolic extracts from the different regions against SPC-A-1 and A549 cells.Results:In this study, the toad skins from Jiangsu province had the highest amount of bufadienolides (472.6 μg/g crude drug) and alkaloids (1.51 mg/g crude drug). Meanwhile, according to the extract, it exhibited the strongest cytotoxic effect against the lung carcinoma cell line (SPC-A-1 cells and A549 cells) with IC50 values of 24.82 ± 0.76 and 23.77 ± 0.63 μg crude drug/mL, respectively.Conclusion:The toad skins that originated from the Jiangsu province, have comparatively greater advantages over samples from other regions as far as active constituent content and potential anti-lung cancer activity is concerned, suggesting that it can be a promising chemotherapeutic agent in lung cancer therapy, in further studies.

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“…Much recent research on bufadienolides has focused on isolation and purification, structure determination, quantitative analysis, and investigation of microbial transformation and quality control 16–20. However, to our knowledge, few studies have been published on the structural characterization of bufadienolides by LC/MS.…”

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confidence: 99%

Systematic screening and characterization of novel bufadienolides from toad skin using ultra‐performance liquid chromatography/electrospray ionization quadrupole time‐of‐flight mass spectrometry

Liu

Xiao

Xue

et al. 2010

Rapid Comm Mass Spectrometry

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During the discovery process of novel compounds, it is of significant importance to differentiate novel from known compounds in crude extracts before starting the time-consuming process of purification. Bufadienolides are the main active components of the skin of the toad Bufo bufo gargarizans Cantor (toad skin), an important traditional Chinese medicine. The fragmentation behavior and mass spectra profiles of bufadienolides standards were investigated using ultra-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC/ESI-Q-TOFMS). Several fragmentation rules were summarized and applied to characterize novel and known bufadienolides in toad skin. Characteristic substituent groups could be identified by both diagnostic ions and their relative abundance. Bufadienolide stereoisomers could be differentiated from positional isomers by comparing fragment abundance profiles. This was used to characterize new stereoisomers for known bufadienolides. A total of 39 bufadienolides were screened out using a systematic method developed in our laboratory. In addition to 19 known bufadienolides, 20 putative novel compounds, including 8 stereoisomers, were characterized. UPLC/Q-TOFMS was demonstrated to be a powerful tool for the characterization of low-abundance bufadienolides in complex samples. This study provides guidelines for the targeted isolation of novel bufadienolides from natural products.

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Microbial transformation of three bufadienolides by Nocardia sp. and some insight for the cytotoxic structure–activity relationship (SAR)

Cited by 36 publications

References 30 publications

Apoptosis-inducing activity of compounds screened and characterized from cinobufacini by bioassay-guided isolation

Apoptosis-inducing activity of compounds screened and characterized from cinobufacini by bioassay-guided isolation

Comparison of toad skins Bufo bufo gargarizans Cantor from different regions for their active constituents content and cytotoxic activity on lung carcinoma cell lines

Systematic screening and characterization of novel bufadienolides from toad skin using ultra‐performance liquid chromatography/electrospray ionization quadrupole time‐of‐flight mass spectrometry

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