Chemistry:Bufagin

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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).
Infobox references

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

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

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:

  • Arenobufagin, from the Argentine toad (Chaunus arenarum, synonym Bufo arenarum);
  • Bufotalin, from the cane toad (Rhinella marina, synonym Bufo marinus);
  • Cinobufagin, from the Chusan Island toad (Bufo gargarizans);
  • Gamabufagin, from the Japanese toad (Bufo japonicus);
  • Marinobufagin, from Bufo rubescens and the cane toad (Bufo marinus);
  • Quercicobufagin, from the oak toad (Anaxyrus quercicus, synonym Bufo quercicus);
  • Regularobufagin, from the square-marked toad (Amietophrynus regularis, synonym Bufo regularis);
  • Vallicepobufagin, from the Gulf Coast toad (Incilius valliceps, synonym Bufo valliceps);
  • Viridibufagin, from the European green toad (Bufo viridis)

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

Synthesis

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.

Effects of bufagins

Some bufagins have effects similar to poisoning by digitalis, having effects on the cardiac muscle, causing ventricular fibrillation. Some also have local anesthetic action. The analgesic effects have also been proven,[8] by acting as Na+/K+-ATPase inhibitors on the binding sites of the cell membrane. The 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.[9][10][11] Some of the bufagin toxins are used in low doses in traditional Chinese medicine for similar applications as digoxin is used for in Western medicine (i.e. treatment of heart conditions such as atrial fibrillation).[12]

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

References

  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): 397–413. doi:10.1039/A815397Y. PMID 9736996. 
  6. ↑ Gao, Huimin; Popescu, Ruxandra; Kopp, Brigitte; Wang, Zhimin (2011). "Bufadienolides and their antitumor activity". Natural Product Reports 28 (5): 953–969. doi:10.1039/C0NP00032A. PMID 21416078. 
  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. PMID 4643019. 
  8. ↑ Wang, G. et al. (1994). "The application of traditional Chinese medicine to the management of hepatic cancerous pain". J Tradit Chin Med 14 (2): 132–138. PMID 7967697. 
  9. ↑ 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. 
  10. ↑ Jing, Y. 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. PMID 8063619. 
  11. ↑ 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. 
  12. ↑ Bick, RJ; Poindexter, BJ; Sweney, RR; Dasgupta, A (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. PMID 12467910. 



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