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Yahuiguo/sandbox/bufagin
Identifiers
Properties
C24H34O5
Molar mass 402.531 g·mol−1
Density 1.240 g/cm3[1]
Melting point 212-213 ˚C[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Bufagin is a toxic steroid C24H34O5[3] obtained from toad's milk, the poisonous secretion of a skin gland on the back of the neck of a large toad (Rhinella marina, synonym Bufo marinus, the cane toad). The toad produces this secretion when it is injured, scared or provoked. Bufagin resembles chemical substances from digitalis in physiological activity and chemical structure.

Bufagin also refers to any of several similar substances found as components of the mixture bufotoxin in secretions of other toads, as well as plants and mushrooms.

History

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The discovery of bufagin has taken place in the fall of 1910, where John Jacob Abel and David I. Macht are investigating the property of unknown substances from a tropical toad, Bufo agua.[4] They collected the "milky secretion" squirted out of toad’s parotid gland due to the control of the central nervous system while it was strongly irritated. They observed the semifluid substance is quickly dried in the air and formed a yellow and hard scales that shared a similar appearance with dried snake venom. After the experiments with the poison, John Jacob Abel and David I. Macht found there are epinephrin and a newly discovered substance exist within the secretion, which they originally gave the name of “bufagin” to this digitalis-like substance. They also quantitatively analyzed the amounts of epinephrin and bufagin in the venom, which showed that 0.734 gram of bufagin with respect to 0.1 gram of epinephrin presented.

Chemistry

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Gamabufagin

Bufagin and bufagins are bufadienolide derivatives. This means they are steroids with a six-membered lactone (α-pyrone) ring attached to ring D (the five-membered one). The difference to digitalis compounds is that the latter have a fix-membered lactone (α-furan) ring that has one carbon atom and one double bond less.

Bufagin is the category name of a large bufadienolide family, there are at least 86 identified bufagins.[5] Examples of bufagins are:

These bufagins, and especially cinobufagin, have given rise to a large number of derivatives evaluated as potential anti-tumor drugs.[6]

Synthesis

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Transformation of bufotalin to cinobufagin

Two structurally similar bufagins can be utilized to develop a synthetic method, which is the transformation of bufotalin to cinobufagin.[7] Cinobufagin is known for its potential as the precursor of many anti-tumor drugs and bufotalin is an important venom found within the cane toad. This synthesis method involves 6 steps.

Symptoms of bufagins

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Cardiology

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Bufagins have effects similar to poisoning by digitalis, which affects the cardiac muscle to cause ventricular fibrillation and some also have local anesthetic action.[8] Bufagins in low doses have the ability to be extremely cardiotoxic that changes the intracellular calcium stores in cardiomyocytes.[9] The unsaturated lactone ring at the C17 position of bufagins can bind to the specific sites on the Na+/K+ ATPase molecule via hydrophobic interactions, which causes the inhibition of such molecules in cardiomyocytes.[10]

Arenobufagins as Na+/K+ ATPase inhibitor

Analgesic

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Bufagins have the analgesic effects by increasing the hepatic blood circulation and decreasing the stagnating blood to reduce pain.[11] Bufagin can be used to replace aspirin or morphine to enhance the pain-relief, anxiety diminishing, and sleep induction. Also, Bufagins with local anesthetic action is more potent with belonged effect by slowing the release of Acetylcholine at the nerve ending.[12]

Oncology

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Bufagins' anti-cancer properties in leukemia and melanoma cells, and the inhibition of the proliferation of prostate cancer cells, have also been investigated in cellular models.[13][14][15] Bufagins also have the potential to enhance the apoptosis in the non-small-cell lung cancer A549 cell by using oxidative stress.[16]

References

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  1. ^ Crowfoot, Dorothy (1935). "X-ray crystallography of the toad poisons bufagin and cinobufagin and of strophanthidin". Chemistry & Industry (London, United Kingdom): 568-9.
  2. ^ Jensen, H.; Evans, E.A. (February 1934). "CHEMICAL STUDIES ON TOAD POISONS". Journal of Biological Chemistry. 104 (2): 307–316. doi:10.1016/S0021-9258(18)75767-0.
  3. ^ ChemicalBook: bufagin
  4. ^ Abel, John J.; Macht, David I. (27 May 1911). "THE POISONS OF THE TROPICAL TOAD, BUFO AGUA: A PRELIMINARY COMMUNICATION". Journal of the American Medical Association. LVI (21): 1531. doi:10.1001/jama.1911.02560210003002.
  5. ^ S. Steyn, Pieter; R. van Heerden, Fanie (1998). "Bufadienolides of plant and animal origin". Natural Product Reports. 15 (4): 397. doi:10.1039/A815397Y.
  6. ^ Gao, Huimin; Popescu, Ruxandra; Kopp, Brigitte; Wang, Zhimin (2011). "Bufadienolides and their antitumor activity". Natural Product Reports. 28 (5): 953. doi:10.1039/C0NP00032A.
  7. ^ Pettit, George R.; Kamano, Yoshiaki (December 1972). "Steroids and related natural products. 78. Bufadienolides. 21. Synthesis of cinobufagin from bufotalin". The Journal of Organic Chemistry. 37 (25): 4040–4044. doi:10.1021/jo00798a015.
  8. ^ Kowalski, Krzysztof; Marciniak, Paweł; Rosiński, Grzegorz; Rychlik, Leszek (1 February 2018). "Toxic activity and protein identification from the parotoid gland secretion of the common toad Bufo bufo". Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 205: 43–52. doi:10.1016/j.cbpc.2018.01.004.
  9. ^ Bick, Roger J; Poindexter, Brian J; Sweney, Roxanne R; Dasgupta, Amitava (27 December 2002). "Effects of Chan Su, a traditional Chinese medicine, on the calcium transients of isolated cardiomyocytes: Cardiotoxicity due to more than Na, K-ATPase blocking". Life Sciences. 72 (6): 699–709. doi:10.1016/S0024-3205(02)02302-0. ISSN 0024-3205.
  10. ^ dos Santos Cruz, Jader; Matsuda, Hiroko (August 1993). "Arenobufagin, a compound in toad venom, blocks Na+K+ pump current in cardiac myocytes". European Journal of Pharmacology. 239 (1–3): 223–226. doi:10.1016/0014-2999(93)90999-X.
  11. ^ Kafle, Arjun; Mohapatra, Sushree Sangita; Reddy, Indrapal (2018). "Bufo toxins: A boon or bane?". International Journal of Fauna and Biological Studies. 5 (1): 98–100. ISSN 2347-2677.
  12. ^ Das, Manika; Mallick, B.N; Dasgupta, S.C; Gomes, A (September 2000). "A sleep inducing factor from common Indian toad (Bufo melanostictus, Schneider) skin extract". Toxicon. 38 (9): 1267–1281. doi:10.1016/S0041-0101(99)00229-9.
  13. ^ Jiun-Yih Yeh; William J. Huang; Shu-Fen Kan; Paulus S. Wang (2002). "Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells". The Prostate. 54 (2): 112–124. doi:10.1002/pros.10172. PMID 12497584. S2CID 36322137.
  14. ^ Jing, Y.; H. Ohizumi; et al. (1994). "Selective inhibitory effect of bufalin on growth of human tumor cells in vitro: association with the induction of apoptosis in leukemia HL-60 cells". Jpn J Cancer Res. 85 (6): 645–651. doi:10.1111/j.1349-7006.1994.tb02408.x. PMC 5919529. PMID 8063619.
  15. ^ Yin, P. H.; Liu, X; Qiu, Y. Y.; Cai, J. F.; Qin, J. M.; Zhu, H. R.; Li, Q (2012). "Anti-tumor activity and apoptosis-regulation mechanisms of bufalin in various cancers: New hope for cancer patients". Asian Pacific Journal of Cancer Prevention. 13 (11): 5339–43. doi:10.7314/apjcp.2012.13.11.5339. PMID 23317181.
  16. ^ . doi:10.1155/2020/8909171. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)CS1 maint: unflagged free DOI (link)
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