Chemistry:Cinobufagin
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| IUPAC name
3β-Hydroxy-14,15β-epoxy-5β-bufa-20,22-dienolid-16β-yl acetate
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| Systematic IUPAC name
(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-Hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiran-2-yl acetate | |
| Other names
Cinobufagin
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| Identifiers | |
3D model (JSmol)
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| Properties | |
| C26H34O6 | |
| Molar mass | 442.552 g·mol−1 |
| Hazards | |
| Main hazards | Toxic |
| GHS pictograms | 
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| GHS Signal word | Danger |
| H300, H310, H330 | |
| P260, P262, P264, P270, P271, P280, P284, P301+310, P302+350, P304+340, P310, P320, P321, P322, P330, P361, P363, P403+233, P405, P501 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
 verify (what is   ?)
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| Infobox references | |
Cinobufagin is a cardiotoxic bufanolide steroid secreted by the Asiatic toad Bufo gargarizans. It has similar effects to digitalis and is used in traditional Chinese medicine.[1]
Isolation and purification
Cinobufagin, as well as other bufadienolides, can be isolated from the traditional Chinese medicine called ChanSu. ChanSu is made from a multitude of chemicals present in Bufo gargarizans secretions. Resibufogenin can be eluted out with silica gel column chromatography, using a 5:1 ratio of cyclohexane to acetone for the solvent in the mobile phase. Subsequently, cinobufagin and bufalin can be separated and purified using an HPLC column with a 72:28 methanol to water solvent. Yang et al. confirmed this method of isolation for cinobufagin with Proton NMR.[2]
Clinical significance
Cinobufagin has been shown to have clinical applications in cancer treatment as well as immunomodulatory and analgesic properties.[citation needed]
In human adrenocortical cells, cinobufagin inhibits the secretion of aldosterone and cortisol. Cinobufagin is able to inhibit the expression of the StAR protein as well as bind the transcription factor SF-1, which normally binds to the promoter for the StAR gene. This results in less StAR protein product and decreased levels of aldosterone and cortisol synthesis. Cinobufagin first binds to a Ca2+/K+ plasma membrane ATPase, subsequently inducing the phosphorylation of extracellular signal-regulated kinases (ERK). Phosphorylated ERK then blocks the SF-1 transcription factor from binding to the promoter region of the StAR gene.
Thus, cinobufagin plays important roles in regulation of steroid synthesis and gene expression. It is speculated that cinobufagin may have therapeutic roles in treatment of Cushing's syndrome and heart failure.[3]
Immunology
In vitro, cinobufagin can stimulate the proliferation of immune cells including splenocytes, peritoneal macrophages, T helper cells and cytotoxic T cells. Additionally cinobufagin can modulate levels of cytokines produced by immune cells. Exposure to cinobufagin increases levels of interferon gamma and tumor necrosis factor alpha while decreasing overall levels of interleukin 4 and interleukin 10.[4]
Analgesic properties
Cinobufagin has been shown to increase pain threshold levels in mice to thermal and mechanical stimuli. It is thought to trigger increased synthesis of β-END and the up-regulation of the mu opioid receptor in mouse tumor tissue thereby leading to pain relief. β-END binds the mu opioid receptor to cause the analgesic effect.[5]
C. elegans can catabolize cinobufagin into five distinct metabolites, each of which has been shown to have cytotoxic effects to HeLa cancer cells.[6]
Cinobufagin can induce cell cycle arrest at the G2 and M phases as well as induce apoptosis in osteosarcoma cells. Potentially, cinobufagin could be used to stop proliferation of osteosarcoma cells as well as to induce apoptosis them. At the protein level, cinobufagin treated osteosarcoma cells showed an increase in the Bax and cleaved-PARP apoptotic proteins, while inhibiting the GSK-3β/NF-κB signaling pathway.[7]
With regards to the induction of apoptosis, cinobufagin has been shown to selectively bind K+/Na+ ATPases in canine kidney cells to trigger a signaling cascade which leads to caspase dependent pathways for apoptosis. It is through the activation of caspases that Cinobufagin can cause apoptosis.[8]
References
- ↑ Yang, Z.; Luo, H.; Wang, H.; Hou H. (2008). "Preparative Isolation of Bufalin and Cinobufagin from Chinese Traditional Medicine ChanSu". Journal of Chromatographic Science 46 (1): 81–85. doi:10.1093/chromsci/46.1.81. PMID 18218193. http://chromsci.oxfordjournals.org/content/46/1/81.full.pdf.
- ↑ Yang, Z.; Luo, H.; Wang, H.; Hou H. (2008). "Preparative Isolation of Bufalin and Cinobufagin from Chinese Traditional Medicine ChanSu". Journal of Chromatographic Science 46 (1): 81–85. doi:10.1093/chromsci/46.1.81. PMID 18218193. http://chromsci.oxfordjournals.org/content/46/1/81.full.pdf.
- ↑ Mei-Mei, Kau; Jiing-Rong Wang; Shiow-Chwen Tsai; Ching-Han Yu; Paulus S Wang (2012). "Inhibitory effect of bufalin and cinobufagin on steroidogenesis via the activation of ERK in human adrenocortical cells". British Journal of Pharmacology 165 (6): 1868–1876. doi:10.1111/j.1476-5381.2011.01671.x. PMID 21913902.
- ↑ "Immunomodulatory effects of cinobufagin isolated from Chan Su on activation and cytokines secretion of immunocyte in vitro.". J Asian Nat Prod Res 13 (5): 383–92. 2011. doi:10.1080/10286020.2011.565746. PMID 21534035.
- ↑ Tao Chen; Wei Hu; Zhang J; Haibo He; Zipeng Gong; Jing Wang; Xueqin Yu; Ting Ai et al. (2013). "A Study on the Mechanism of Cinobufagin in the Treatment of Paw Cancer Pain by Modulating Local β-Endorphin Expression In Vivo.". Evidence-Based Complementary and Alternative Medicine 2013: 1–9. doi:10.1155/2013/851256. PMID 24187573.
- ↑ Li Qiao; Yu-zhi Zhou; Zhang J; Xiu-lan Qi; Li-hong Lin; Huan Chen; Li-yan Pang; Yue-hu Pei (2007). "Biotransformation of Cinobufagin by Cunninghamella elegans". The Journal of Antibiotics 60 (4): 261–264. doi:10.1038/ja.2007.32. PMID 17456977. http://www.nature.com/ja/journal/v60/n4/pdf/ja200732a.pdf.
- ↑ "The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells.". Toxicology Letters 218 (2): 129–36. 2013. doi:10.1016/j.toxlet.2012.11.006. PMID 23164673.
- ↑ Akimova OA; Bagrov AY; Lopina OD; Kamernitsky AV; Tremblay J; Hamet P; Orlov SN (2005). "Cardiotonic steroids differentially affect intracellular Na+ and [Na+]i/[K+]i-independent signaling in C7-MDCK cells.". The Journal of Biological Chemistry 280 (1): 832–839. doi:10.1074/jbc.M411011200. PMID 15494417.
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