Cinobufagin

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]

Cinobufagin
Names
IUPAC name
3β-Hydroxy-14,15β-epoxy-5β-bufa-20,22-dienolid-16β-yl acetate
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
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.164.680
EC Number
  • 636-927-8
KEGG
UNII
  • InChI=1S/C26H34O6/c1-14(27)31-22-21(15-4-7-20(29)30-13-15)25(3)11-9-18-19(26(25)23(22)32-26)6-5-16-12-17(28)8-10-24(16,18)2/h4,7,13,16-19,21-23,28H,5-6,8-12H2,1-3H3/t16-,17+,18+,19-,21+,22-,23-,24+,25-,26-/m1/s1 ☒N
    Key: SCULJPGYOQQXTK-OLRINKBESA-N ☒N
  • InChI=1/C26H34O6/c1-14(27)31-22-21(15-4-7-20(29)30-13-15)25(3)11-9-18-19(26(25)23(22)32-26)6-5-16-12-17(28)8-10-24(16,18)2/h4,7,13,16-19,21-23,28H,5-6,8-12H2,1-3H3/t16-,17+,18+,19-,21+,22-,23-,24+,25-,26-/m1/s1
    Key: SCULJPGYOQQXTK-OLRINKBEBZ
  • O=C\1O\C=C(/C=C/1)[C@@H]4[C@@]6(C)CC[C@H]3[C@@H](CC[C@@H]2C[C@@H](O)CC[C@@]23C)[C@]65O[C@@H]5[C@@H]4OC(=O)C
Properties
C26H34O6
Molar mass 442.552 g·mol−1
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Toxic
GHS labelling:
GHS06: Toxic
Danger
H300, H310, H330
P260, P262, P264, P270, P271, P280, P284, P301+P310, P302+P350, P304+P340, P310, P320, P321, P322, P330, P361, P363, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

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.

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
  1. Yang, Z.; Luo, H.; Wang, H.; Hou H. (2008). "Preparative Isolation of Bufalin and Cinobufagin from Chinese Traditional Medicine ChanSu" (PDF). Journal of Chromatographic Science. 46 (1): 81–85. doi:10.1093/chromsci/46.1.81. PMID 18218193.
  2. Yang, Z.; Luo, H.; Wang, H.; Hou H. (2008). "Preparative Isolation of Bufalin and Cinobufagin from Chinese Traditional Medicine ChanSu" (PDF). Journal of Chromatographic Science. 46 (1): 81–85. doi:10.1093/chromsci/46.1.81. PMID 18218193.
  3. 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. PMC 3372836. PMID 21913902.
  4. Wang XL, Zhao GH, Zhang J, Shi QY, Guo WX, Tian XL, Qiu JZ, Yin LZ, Deng XM, Song Y (2011). "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. doi:10.1080/10286020.2011.565746. PMID 21534035. S2CID 205679985.
  5. Tao Chen; Wei Hu; Zhang J; Haibo He; Zipeng Gong; Jing Wang; Xueqin Yu; Ting Ai; Ling Zhan (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. PMC 3800629. PMID 24187573.
  6. 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" (PDF). The Journal of Antibiotics. 60 (4): 261–264. doi:10.1038/ja.2007.32. PMID 17456977.
  7. Yin JQ, Wen L, Wu LC, Gao ZH, Huang G, Wang J, Zou CY, Tan PX, Yong BC, Jia Q, Shen JN (2013). "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. doi:10.1016/j.toxlet.2012.11.006. PMID 23164673.
  8. 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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