Jump to content

User:Nkaltenh/sandbox

From Wikipedia, the free encyclopedia
Nkaltenh/sandbox
Names
IUPAC name
3β,14-Dihydroxy-5β-bufa-20,22-dienolide
Systematic IUPAC name
4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-3a,7-Dihydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2H-pyran-2-one
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
UNII
  • InChI=1S/C24H34O4/c1-22-10-7-17(25)13-16(22)4-5-20-19(22)8-11-23(2)18(9-12-24(20,23)27)15-3-6-21(26)28-14-15/h3,6,14,16-20,25,27H,4-5,7-13H2,1-2H3/t16-,17+,18-,19+,20-,22+,23-,24+/m1/s1
    Key: QEEBRPGZBVVINN-BMPKRDENSA-N
  • C[C@]12CC[C@@H](C[C@H]1CC[C@@H]3[C@@H]2CC[C@]4([C@@]3(CC[C@@H]4c5ccc(=O)oc5)O)C)O
Properties
C24H34O4
Molar mass 386.532 g·mol−1
Hazards
GHS labelling:
GHS06: Toxic
Danger
H300
P264, P270, P301+P310, P321, P330, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Tracking categories (test):

Bufalin is a cardiotonic steroid toxin[1] originally isolated from Chinese toad venom, which is a component of some traditional Chinese medicines.[2][3] Bufalin acts as an inhibitor on Na+/K+ ATPase, an ion pump which regulates cellular ion concentration. [4][5] This is the reason for its cardiotonic effect, as the ion pump needs to regulate these ions for the heart to work effectively. [4][5] The specific structure of bufalin is a cis-trans-cis fused steroid ring, exhibiting both polar and nonpolar character, which is important for how it interacts with the pump. [6] Additionally, its lactone is vital for the affinity due to interactions with potassium ions in the cationic site of Na+/K+ ATPase.[6]. The median lethal dose is contested, but is between 0.74-2.2 mg/kg. [7]. Bufalin is usually consumed through eating the meat, gallbladder, skin, or eggs of the toad, but it can also be consumed through other methods. [5] Overconsumption of bufalin causes serious symptoms like gastrointestinal issues, cardiovascular difficulties, hallucinations, and even death. [8]

Biochemistry

[edit]

Mechanism of action

[edit]

Bufalin acts on the sodium and potassium Adenosine 5'-TriPhosphatase as an antagonist. [6] By inhibiting these pumps, they prevent depolarization of sodium and potassium across the cell membrane, resulting in vasoconstriction. [4] However, it has also been proposed that an increase of calcium ions caused by a decrease in sodium and calcium ion exchange into vascular smooth muscle cells causes this vasoconstriction. [4] As a result, blood pressure and heart rate increase with bufalin consumption, and this can lead to cardiotoxicity. [4][5]

Structure Activity Relationship

[edit]

The main structural core of bufalin is a cis-trans-cis fused steroid with methyl, hydroxy, and lactone substituents. [6] These substituents are away from the plane of the ring, making them all β, which is important for how the steroid interacts with Na+/K+ ATPase. It was noted by researchers that the α surface of the steroid (concave face) interacts with the nonpolar portion, whereas the β surface interacts with the polar surface of Na+/K+ ATPase. [6] Additionally, the lactone substituent binds near the cation binding site, however, there are no polar interactions that occur between the lactone and the pump due to this area being nonpolar. Interestingly, researchers discovered that this lactone moiety directly interacts with potassium ions when in the cation binding site. [6] This explains why bufalin shows a stronger affinity to the pump when potassium ions are present, and why the lactone orients itself into this nonpolar portion of the pump. [6]

Labeled surface interactions of bufalin with ATPase

Toxicity and Symptoms

[edit]

The reported LD50 of bufalin injected in a nude mouse model was 2.2 mg/kg. Yet, this value has been recently reported as 0.74 mg/kg in mice. [7] Bufalin is commonly consumed orally via the toads meat, eggs, skin, or gallbladder, but other methods of consumption are common (e.g. aphrodisiacs containing the toxin, medicines, tadpoles, liquor containing the skin, and toad skin secretion). [5] Symptoms can vary when consumed, but gastrointestinal issues such as nausea, vomiting, and diarrhea are the most common. Along with these issues come cardiovascular problems, and sometimes even hallucinations. [5][8] In serious cases, fatality can occur from complications, usually from the cardiovascular issues. [5][8]

Chemical Synthesis

[edit]

In 1969, Franz Sondheimer and coworkers first synthesized bufalin from 14α-hydroxycortexolone. Over 25 steps, they synthesized the compound, recovering 50% in the last step of the reaction. [9]

Total synthesis of bufalin by Sondheimer and coworkers [9]

Some notable steps include the selective reduction of the alkene using 50 equivalents of potassium metal in liquid ammonia and the creation of the 6-membered lactone via Vilsmeier-Haack reaction, followed by hydrolysis of the vinylogous ester with sodium hydroxide in ethanol, and finally forming it when subjecting the intermediate to a Reformatsky reaction. [9] A more recent synthesis by Qunfei Zhao and coworkers completes this synthesis over 7 steps starting from androstenedione. The group was able to successfully synthesize bufalin in an overall 6-10% yield, not utilizing any protecting groups, unlike what Sondheimer and coworkers had to do. [10]

Research

[edit]

Bufalin has in vitro antitumor effects against various malignant cell lines, including hepatocellular[11] and lung carcinoma.[12] However, as with other bufadienolides, its potential use is hampered by its cardiotoxicity.[13]

References

[edit]
  1. ^ A Dasgupta, P Datta (1998). "Rapid detection of cardioactive bufalin toxicity using fluorescence polarization immunoassay for digitoxin". Ther Drug Monit. 20 (1): 104–108. doi:10.1097/00007691-199802000-00019. PMID 9485564.
  2. ^ "Datasheet: Bufotalin sc-sc-200136" (PDF). Santa Cruz Biotechnology, Inc.
  3. ^ Okada, Masahiro; Suga, Toshiro; et al. (April 1960). "Pharmacology of the principles isolated from Senso (Ch'an Su) the dried venom of the Chinese toad (IV)" (PDF). Asian Medical Journal. 3 (4): 155–160.
  4. ^ a b c d e Pamnani, M B; Chen, S; Bryant, H J; Schooley, J F; Eliades, D C; Yuan, C M; Haddy, F J (September 1991). "Effects of three sodium-potassium adenosine triphosphatase inhibitors". Hypertension. 18 (3): 316–324. doi:10.1161/01.HYP.18.3.316.
  5. ^ a b c d e f g Liu, Yuhang; Zhang, Jinlong; Wang, Binbin; Zheng, Feifei; Yan, Jie (15 February 2025). "Epidemiological patterns and therapeutic approaches of toad toxin poisoning in a retrospective case study". Scientific Reports. 15 (1): 5586. doi:https://doi.org/10.1038/s41598-025-89809-0. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  6. ^ a b c d e f g Laursen, Mette; Gregersen, Jonas Lindholt; Yatime, Laure; Nissen, Poul; Fedosova, Natalya U. (10 February 2015). "Structures and characterization of digoxin- and bufalin-bound Na + ,K + -ATPase compared with the ouabain-bound complex". Proceedings of the National Academy of Sciences. 112 (6): 1755–1760. doi:10.1073/pnas.1422997112.
  7. ^ a b Cheng, Chien-shan; Wang, Jiaqiang; Chen, Jie; Kuo, Kuei Ting; Tang, Jian; Gao, Huifeng; Chen, Lianyu; Chen, Zhen; Meng, Zhiqiang (11 April 2019). "New therapeutic aspects of steroidal cardiac glycosides: the anticancer properties of Huachansu and its main active constituent Bufalin". Cancer Cell International. 19 (1): 92. doi:https://doi.org/10.1186/s12935-019-0806-1. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  8. ^ a b c Trakulsrichai, Satariya; Chumvanichaya, Kritsada; Sriapha, Charuwan; Tongpoo, Achara; Wananukul, Winai (16 December 2020). "Toad Poisoning: Clinical Characteristics and Outcomes". Therapeutics and Clinical Risk Management. 16: 1235–1241. doi:https://doi.org/10.2147/TCRM.S272863. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  9. ^ a b c Sondheimer, Franz; McCrae, W.; Salmond, W. G. (1 February 1969). "Synthesis of bufadienolides. Synthesis of bufalin and resibufogenin". Journal of the American Chemical Society. 91 (5): 1228–1230. doi:https://doi.org/10.1021/ja01033a039. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  10. ^ Yu, Shaopeng; Zhang, Qiuheng; Zhong, Xueqing; Wang, Chao; Shi, Wenqing; Zhuang, Jiahua; Zhang, Rui; Jin, Fangjie; Zhang, Jiange; Zhao, Qunfei; Chen, Gu-Zhou; Ye, Wenbo; Lin, Guo-Qiang (15 November 2024). "Scalable Protecting-Group-Free Total Synthesis of Resibufogenin and Bufalin". Organic Letters. 26 (45): 9704–9709. doi:https://doi.org/10.1021/acs.orglett.4c03433. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  11. ^ Zhang ZJ (Feb 2014). "Bufalin attenuates the stage and metastatic potential of hepatocellular carcinoma in nude mice". J Transl Med. 12: 57. doi:10.1186/1479-5876-12-57. PMC 4015709. PMID 24581171.
  12. ^ Wu SH (2014). "Bufalin induces cell death in human lung cancer cells through disruption of DNA damage response pathways". Am J Chin Med. 42 (3): 729–42. doi:10.1142/S0192415X14500475. PMID 24871662.
  13. ^ Ma H (Jul 2012). "The novel antidote Bezoar Bovis prevents the cardiotoxicity of Toad (Bufo bufo gargarizans Canto) Venom in mice". Exp Toxicol Pathol. 64 (5): 417–23. doi:10.1016/j.etp.2010.10.007. PMID 21084181.


Bufotoxins are a family of toxic steroid lactones or substituted tryptamines of which some are toxic. They occur in the parotoid glands, skin, and poison of many toads (Bufonidae family) and other amphibians, and in some plants and mushrooms.[1][2][3] The exact composition varies greatly with the specific source of the toxin.

Composition

[edit]
Chemical structure of one of the main components of bufotoxin, a conjugate of bufagin with suberylarginine. This component is itself sometimes called bufotoxin.

Bufotoxins can contain 5-MeO-DMT, bufagins, bufalin, bufotalin, bufotenin, bufothionine, dehydrobufotenine, epinephrine, norepinephrine, and serotonin. Some authors have also used the term bufotoxin to describe the conjugate of a bufagin with suberylarginine.[4]

The toxic substances found in toads can be divided by chemical structure in two groups:

Bufadienolides

[edit]

Bufadienolides, which are cardiac glycosides (e.g., bufotalin, bufogenin), are undesirable compounds commonly excreted from toads that may be fatal if consumed. Their general structure is a 24-carbon steroid with a 6-membered lactone ring at the 17th carbon. [5] Usually, bufadienolides are broken up into the free and conjugated versions, with the only difference being esterification of the hydroxy group at carbon 3. [5]. These classes of compounds are usually associated with their strong inhibition of Na+/K ATPase [5], but they have also been associated with their anti-tumor and inflammatory properties. [6]

[edit]

Tryptamine-related substances (e.g., bufotenin), are sought after for entheogenic and/or recreational purposes by some individuals. The most popular of these compounds is bufotenin, which is chemically similar to serotonin, [7] and 5-MeO-DMT. [8] Both compounds affect the central nervous system, giving off effects similar to LSD due to their effect to inhibit 5-HT receptors. [8][9] At high enough doses, bufotenin can exhibit similar side effects to bufalin including nausea, vomiting, and gastrointestinal problems. [7] However, the practice of using these substances derived from animals for spiritual experiences or responsible drug use may raise ethical concerns about the potential suffering inflicted on the animal.

Species

[edit]
See also: List of poisonous animals

Toads known to secrete bufotoxins.[10]

Toads frequently "milked"

[edit]

Despite being a frequent target for milking, these toads still carry cardio toxic bufotoxins which have been linked to deaths.

Other toads

[edit]

The effects of the bufotoxins in these toads are not well understood.

Extraction

[edit]

Extract from the skin of certain Asian toads, such as Bufo bufo gargarizans and Bufo melanostictus, is often found in certain Chinese folk remedies. The Pharmacopoeia of the People's Republic of China (ChP) considers the two species valid sources of toad poison (Chinese: 蟾酥; pinyin: Chánsū; Latin: bufonis venenum), and requires the dry product to contain at least 6% of cinobufagin and resibufogenin combined by weight. The extract is obtained by squeezing the parotoid glands of caught, washed toads for a white venom and drying; the final dried poison is usually brown, with a chunk or flake form.[11]

Human poisoning

[edit]

Poisoning from toad toxin is rare but can kill.[12] It can occur when someone drinks toad soup, eats toad meat or toad eggs, or swallows live toads.[12][13] It can also happen when someone deliberately takes commercial substances made with toad toxins.[13] These go under names including "Kyushin", "Chan Su" (marketed as a painkiller,[13] topical anesthetic or cardiac treatment[14]), "Rockhard" and "Love Stone" (marketed as aphrodisiacs).[13]

"Chan Su" (literally "toad venom") is often adulterated with standard painkillers, such as paracetamol, promethazine and diclofenac. It may be ingested or injected.[15]


Symptoms of Intoxication

[edit]

Symptoms may vary depending on certain factors such as the size and age of the victim. Other than the first, more benign symptoms (such as a tingling or burning sensation in the eyes, mucous membranes, or in exposed wounds), the most frequently described symptoms in the medical literature are :

One epileptic episode caused by Bufotoxins was observed in a 5-year old child, minutes after they had placed a Bufo alvarius in their mouth. The child was successfully treated with diazepam and phenobarbital.[16]

In extreme cases following ingestion of mucus or skin of the toad, death generally occurs within 6 and 24 hours. Victims surviving past 24 hours generally will recover.

References

[edit]
  1. ^ Siperstein MD, Murray AW, Titus E (March 1957). "Biosynthesis of cardiotonic sterols from cholesterol in the toad, Bufo marinus". Archives of Biochemistry and Biophysics. 67 (1): 154–60. doi:10.1016/0003-9861(57)90254-0. PMID 13412129.
  2. ^ Lincoff, Gary; Mitchel, Duane H. (1977). Toxic and Hallucinogenic Mushroom Poisoning: A Handbook for Physicians and Mushroom Hunters. New York: Van Nostrand Reinhold. ISBN 978-0-442-24580-1.[page needed]
  3. ^ Kißmer, B.; Wichtl, M. (1986). "Bufadienolide aus Samen von Helleborus odorus" [Bufadienolides from the Seeds of Helleborus odorus]. Planta Medica (in German). 52 (2): 152–3. doi:10.1055/s-2007-969103. S2CID 84240708.
  4. ^ Chen KK, Kovaríková A (December 1967). "Pharmacology and toxicology of toad venom". Journal of Pharmaceutical Sciences. 56 (12): 1535–41. doi:10.1002/jps.2600561202. PMID 4871915.
  5. ^ a b c Zou, Denglang; Wang, Qiqi; Chen, Tao; Sang, Duocheng; Yang, Tingqin; Wang, Yuhan; Gao, Mengze; He, Fangfang; Li, Yulin; He, Liangliang; Longzhu, Duojie (19 October 2022). "Bufadienolides originated from toad source and their anti-inflammatory activity". Frontiers in Pharmacology. 13. doi:https://doi.org/10.3389/fphar.2022.1044027. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  6. ^ Asrorov, Akmal M.; Kayumov, Muzaffar; Mukhamedov, Nurkhodja; Yashinov, Ansor; Mirakhmetova, Ziyoda; Huang, Yongzhuo; Yili, Abulimiti; Aisa, Haji Akber; Tashmukhamedov, Mugrajitdin; Salikhov, Shavkat; Mirzaakhmedov, Sharafitdin (2023). "Toad venom bufadienolides and bufotoxins: An updated review". Drug Development Research. 84 (5): 815–838. doi:https://doi.org/10.1002/ddr.22072. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  7. ^ a b Vigerelli, Hugo; Sciani, Juliana Mozer; Eula, Maria Andrea Camarano; Sato, Luciana Almeida; Antoniazzi, Marta M.; Jared, Carlos; Pimenta, Daniel C. (2018). "Biological Effects and Biodistribution of Bufotenine on Mice". BioMed Research International. 2018 (1): 1032638. doi:https://doi.org/10.1155/2018/1032638. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  8. ^ a b Liu, Yuhang; Zhang, Jinlong; Wang, Binbin; Zheng, Feifei; Yan, Jie (15 February 2025). "Epidemiological patterns and therapeutic approaches of toad toxin poisoning in a retrospective case study". Scientific Reports. 15 (1): 5586. doi:https://doi.org/10.1038/s41598-025-89809-0. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  9. ^ Neumann, Joachim; Schulz, Nils; Fehse, Charlotte; Azatsian, Karyna; Čináková, Aneta; Marušáková, Margaréta; Hofmann, Britt; Gergs, Ulrich (1 July 2023). "Cardiovascular effects of bufotenin on human 5-HT4 serotonin receptors in cardiac preparations of transgenic mice and in human atrial preparations". Naunyn-Schmiedeberg's Archives of Pharmacology. 396 (7): 1471–1485. doi:https://doi.org/10.1007/s00210-023-02414-8. {{cite journal}}: Check |doi= value (help); External link in |doi= (help)
  10. ^ 国家药典委员会 (2015). 中华人民共和国药典 [Pharmacopoeia of the People's Republic of China] (in Chinese). Vol. 1 (10 ed.). 中国医药科技出版社. p. 333. ISBN 9787506773379. entries: 蟾酥 bufonis venenum
  11. ^ a b Kuo, HY; Hsu, CW; Chen, JH; Wu, YL; Shen, YS (March 2007). "Life-threatening episode after ingestion of toad eggs: a case report with literature review". Emergency Medicine Journal. 24 (3): 215–6. doi:10.1136/emj.2006.044602. PMC 2660035. PMID 17351232.
  12. ^ a b c d Cartwright, Megan (29 June 2015). "These Men Died Trying to Achieve Epic Erections". Slate Magazine. Retrieved 22 April 2021.
  13. ^ Kostakis, Chris; Byard, Roger W. (2009-07-01). "Sudden death associated with intravenous injection of toad extract". Forensic Science International. 188 (1): e1 – e5. doi:10.1016/j.forsciint.2009.02.006. ISSN 0379-0738. PMID 19303230.
  14. ^ Trakulsrichai, S; Chumvanichaya, K; Sriapha, C; Tongpoo, A; Wananukul, W (2020). "Toad Poisoning: Clinical Characteristics and Outcomes". Therapeutics and Clinical Risk Management. 16: 1235–1241. doi:10.2147/TCRM.S272863. PMC 7752649. PMID 33363378.
  15. ^ Hitt M, Ettinger DD. Toad toxicity. N Engl J Med; 1986; 314:1517
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Nkaltenh/sandbox&oldid=1289256153"