Chemistry:Convallatoxin

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Convallatoxin
Convallatoxin.svg
Convallatoxin 3D BS.png
Names
IUPAC name
5,14-Dihydroxy-19-oxo-3β-(α-L-rhamnopyranosyloxy)-5β-card-20(22)-enolide
Systematic IUPAC name
(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-3a,5a-Dihydroxy-11a-methyl-1-(5-oxo-2,5-dihydrofuran-3-yl)-7-{[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexadecahydro-9aH-cyclopenta[a]phenanthrene-9a-carbaldehyde
Other names
Strophanthin 3alpha-1-rhamnoside; Strophanthidin alpha-l-rhamnopyranoside; Strophanthidin a-l-rhamnopyranoside; Corglycon (Russian: Коргликон); 20(22),5beta-cardenolid-19-al-3beta,5beta,14beta-triol-3beta-d-[a-1-rhamnopyranoside]; 5Beta,20[22]-cardenolide-19-one-3beta,5alpha,14-triol-3-[6-deoxy-alpha-l-mannopyranosyl]; 3Beta,5alpha,14-trihydroxy-19-oxo-5beta,20[22]-cardenolide-3-[6-deoxy-alpha-l-mannopyranosyl]
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
EC Number
  • 208-086-3
UNII
Properties
C29H42O10
Molar mass 550.645 g·mol−1
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

Convallatoxin is a glycoside extracted from Convallaria majalis.

History

Convallatoxin is a natural cardiac glycoside that can be found, among others, in the plant lily of the valley (Convallaria majalis). Legend says that Apollo gave this plant to Asclepios, the Greek god of healing.[1] Lily of the valley has indeed been used medicinally to treat illness,[2] all going back to medieval times. Convallatoxin has a similar therapeutic target and effect as digitalis, so it was used by medieval herbalists as a substitute for foxglove in treatment.[3][4] It is mostly administered because it strengthens the heartbeat, while also slowing and regulating the heart rate.[3] In 2011, the lily of the valley was used in the US television show Breaking Bad. This made the plant, and its compound convallatoxin, quite well known by the general public as fatal.[5]

Structure and reactivity

The systematic name of the organic compound convallatoxin is as follows: (1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-3a,5a-dihydroxy-11a-methyl-1-(5-oxo-2,5-dihydrofuran-3-yl)-7-{[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexadecahydro-9aH-cyclopenta[a]phenanthrene-9a-carbaldehyde. A shorter semisystematic IUPAC name is 5,14-dihydroxy-19-oxo-3β-(α-L-rhamnopyranosyloxy)-5β-card-20(22)-enolide. The structure of convallatoxin consists of strophanthidin and has a 6-deoxy-α-L-mannopyranosyl group attached at position 3.[6]

Convallatoxin can donate a hydrogen bond at five places and it can accept a hydrogen bond on ten accounts.[6] Its melting point lies between 235 and 242 degrees Celsius and the compound is soluble in alcohol, acetone and slightly in chloroform, ethyl acetate and water.[7]

Since convallatoxin is structurally similar to digoxin, research has been done to determine if convallatoxin in serum can be detected with LOCI digoxin assays.[4] This showed that the compound has significant cross-reactivity with the used antibody and that it causes bidirectional interference in the digoxin assay. So, convallatoxin can indeed be detected with a LOCI digoxin assay. It may also be possible that convallatoxin cross-reacts with the antidigoxin antibody used in other commercially available digoxin assays, but this should be investigated further. Furthermore, the antigen Digibind does also bind convallatoxin in vitro. This could possibly be used in treatment of convallatoxin poisoning.[4]

Synthesis

Even though convallatoxin can be found in nature, it is also synthesized by manufacturers. This can be done via the Koenigs-Knorr method,[8] in which strophanthidin is glycosylated with 2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl bromide.[9][10] These two compounds are the precursors of convallatoxin. After alkaline hydrolysis, extraction from strophanthidin residues and crystallization of isopropanol, the reaction product is liberated. This reaction product is convallatoxin. When using 10 grams of strophanthidin, 13.6 grams of convallatoxin can be produced.[9]

Mechanism of action and efficacy

Convallatoxin is a digitalis like compound (DLC), which is mainly used as a cardiac glycoside since it can inhibit the Na+,K+-ATPase in congestive heart failure or arrythmias,[11][12][13][14][15] which causes an inotropic effect,[14][16] same as many other digitalis like compounds. The Na+,K+-ATPase creates the ion gradient between the intra- and extracellular domains of a cell. It does this by transporting three sodium ions out of and two potassium ions into the cell.[17] If the Na+,K+-ATPase is inhibited, sodium will accumulate in the cell, preventing the sodium-calcium exchanger to work during diastole. If calcium accumulates in cardiac myocytes, the uptake of calcium into the sarcoplasmic reticulum (SR) is increased. Thus, when stimulation of the cardiac muscle occurs, the SR releases higher levels of calcium, which increases the contractility of the myocytes.[17] The increased release of calcium also increases the refractory period of the atrioventricular (AV) node, regulating the heart beat cycle [18] in patients with arrythmia.

In lung, colon and breast cancer cells, convallatoxin shows great effects at nano doses.[15][19][20][21] It has been shown to inhibit cell proliferation, invasion and migration of cancer cells. The underlying mechanisms of this are not fully known. However, it has been demonstrated that convallatoxin induces apoptosis and autophagy at a dose of 10 nM per 3 days.[13] It was also shown to inhibit angiogenesis through autophagy and apoptosis at concentrations of 2-4 nM.[13] Autophagy is induced in human cervical carcinoma cells, or HeLa cells by convallatoxin blocking the mTOR signalling pathway. This signalling pathway usually inhibits autophagy in cells. Convallatoxin induces apoptosis by increasing caspase-3 and PARP cleavage. These proteins induce programmed cell death when activated by cleavage.[13] It is not entirely clear if the induction of apoptosis and autophagy is related to the inhibitory effects of convallatoxin on the Na+, K+-ATPase pump. However, a dose of 10 nM convallatoxin can reduce A549 non small cell lung cancer cells by inhibiting the Na+,K+-ATPase.[15][20] Numbers differ per experiment. In colon cancer a LD50 of 50 nM is shown.[19] In MCF-7 derived breast cancer cells an IC50 dose of 10 nM over a long time (exposure 24 h) show 27.65 ± 8.5 or over an even longer time (exposure 72 h), 5.32 ± 0.15 are observed.[21]

There are many more potential therapeutic uses for convallatoxin, for example against cystic fibrosis and neurodegenerative diseases.[22] It has also been demonstrated to inhibit viral infection and replication.[23] For example, convallatoxin can be used as a treatment for the Human Cytomegalovirus. It will inhibit the Na+-K+-ATPase pump which decreases the sodium concentration outside the cell, and thus limiting cotransport of methionine and sodium into the cell, disabling protein synthesis.[24] A dose of 0.01 μM already has a great efficacy against the cytomegalovirus, but at a dose of 50 nM or less a great potency is also shown that can last up to 4 hours.[24]

Convallatoxin is thus quite an efficient drug, showing effects with small doses in treatment of multiple diseases. It is excreted by P-glycoprotein and an affinity of 1.07 ± 0.24 mM and a Vmax of 5.2 ± 0.4 mmol mg/protein/min were determined. Excretion of convallatoxin is mainly by the kidneys (a clogP of about -0.7).[25][26]

Metabolism

Convallatoxin is mainly metabolised in the liver by the conversion of convallatoxin into convallatoxol.[27] For this, the aldehyde (-CHO) group attached to C¬10 is reduced to an alcohol group (-CH2OH) by cytochrome P450 reductase (CYP450).[28] This is a phase I metabolism reaction. However, further modification through a phase II reaction of convallatoxin has not been found.[29] The reduction of convallatoxin increases its polarity, thus enabling the compound to be excreted more readily. This form of convallatoxin metabolism can be found in rats, however is not present in guinea pigs and only traces of convallatoxol can be found in cats.[30]

Toxicity

Convallatoxin has a very small therapeutic index (40-50 nM) i.e. the margin is narrow between a therapeutic dose and an overdose giving rise to symptoms of poisoning. Even so, the cytotoxicity of convallatoxin is mainly time-dependent.

At an increased plasma level, DLCs (including convallatoxin) toxicity symptoms include dizziness, fatigue, nausea, loss of appetite, vision disturbance, vomiting, hypertension, arrythmia, cardiac arrest, coma, abdominal pain and convulsions, heart failure or death.[11][12][25]

Effects on animals

On certain animals, convallatoxin has quite interesting effects. The lifespan of C. elegans, a nematode, can be expanded by convallatoxin.[31] About 20 μM of convallatoxin shows no toxicity and can expand the lifespan of the worm by 16.3% due to certain mechanisms, including improvement of pharyngeal pumping, locomotion, reduced lipofuscin accumulation and ROS.[31]

Where the convallatoxin has quite positive effects on nematodes, it is extra poisonous to cats.[32] It causes nephrotoxicity and acute renal failure, but at what dose exactly is not known. Symptoms are salivation, vomiting, anorexia and depression. It can be treated with dialysis, when diuresis is started before the acute renal failure.[32]

References

  1. ↑ Hill, K. "Guide to the Medicinal Plant Garden". Indiana Medical History Museum. https://www.imhm.org/resources/Documents/Binder1_MPG_Guide_2010_sfs.pdf. 
  2. ↑ van der Bijl Jr., P; van der Bijl Sr., P (2012). "Cardiovascular Toxicities of Herbal Products: An Overview of Selected Compounds". Toxicology of Herbal Products. Cham, Switzerland: Springer Nature. pp. 363–383. 
  3. ↑ 3.0 3.1 Breverton, T (2012). Breverton's Complete Herbal: A book of remarkable plants and their uses.. London: Lyons Press. 
  4. ↑ 4.0 4.1 4.2 Welsh, K J; Huang, R S P; Actor, J K; Dasgupta, A (2019-03-05). "Rapid Detection of the Active Cardiac Glycoside Convallatoxin of Lily of the Valley Using LOCI Gigoxin Assay". American Journal of Clinical Pathology 142 (3): 307–312. doi:10.1309/AJCPCOXF0O5XXTKD. PMID 25125619. 
  5. ↑ Schönsee, C (2018-04-16). "Convallatoxin - the toxin of wild garlic's deadly doppelgänger". https://natoxaq.ku.dk/toxin-of-the-week/convallatoxin/. 
  6. ↑ 6.0 6.1 PubChem. "Convallatoxin" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/441852. 
  7. ↑ Windholz, M (1976). The Merck Index: an encyclopedia of chemicals and drugs. Rahway, USA: Merck & Co.. pp. 323. 
  8. ↑ Koenigs, W; Knorr, E (1901). "Ueber einige Derivate des Traubenzuckers un der Galactose". Berichte der Deutschen Chemischen Gesellschaft 34 (1): 957–981. doi:10.1002/cber.190103401162. https://zenodo.org/record/1425998. 
  9. ↑ 9.0 9.1 Makarevich, IF; Terno, IS (1988). "Synthesis of convalloside". Chemistry of Natural Compounds 24 (3): 323–325. doi:10.1007/BF00598579. 
  10. ↑ Reyle, K; Meyer, K; Reichstein, T (1950). "Partialsynthese von Convallatoxin". Helvetica Chimica Acta 33 (6): 1541–1546. doi:10.1002/hlca.19500330621. 
  11. ↑ 11.0 11.1 Alexandre, J; Foucault, A; Coutance, G; Scanu, P; Milliez, P (2012). "Digitalis intoxication induced by an acute accidental poisoning by lily of the valley.". Circulation 125 (8): 1053–1055. doi:10.1161/circulationaha.111.044628. PMID 22371443. 
  12. ↑ 12.0 12.1 Wink, M (2010). "Mode of action and toxicology of plant toxins and poisonous plants". Julius-Kühn-Archiv 421: 93. 
  13. ↑ 13.0 13.1 13.2 13.3 Yang, SY; Kim, NH; Cho, YS; Lee, H; Kwon, HJ (2014). "Convallatoxin, a dual inducer of autophagy and apoptosis, inhibits angiogenesis in vitro and in vivo". PLOS ONE 9 (3): e91094. doi:10.1371/journal.pone.0091094. PMID 24663328. Bibcode: 2014PLoSO...991094Y. 
  14. ↑ 14.0 14.1 Cheng, CJ; Lin, CS; Chang, LW; Lin, SH (2006). "Perplexing hyperkalaemia". Nephrology Dialysis Transplantation 21 (11): 3320–3323. doi:10.1093/ndt/gfl389. PMID 16968727. 
  15. ↑ 15.0 15.1 15.2 Schneider, NFZ; Silva, IT; Perish, L; de Carvalho, A; Rocha, SC; Marostica, L; Ramos, ACP; Taranto, AG et al. (2017). "Cytotoxic effects of the cardenolide convallatoxin and its Na, K-ATPase regulation". Molecular and Cellular Biochemistry 428 (1–2): 23–29. doi:10.1007/s11010-016-2914-8. PMID 28176244. 
  16. ↑ Everett, JM; Konjima, YA; Davis, B; Wahed, A; Dasgupta, A (2015). "The iDigoxin assay is more sensitive than LOCI digoxin assay for rapid detection of convallatoxin, the active cardiac glycoside of lily of the valley". Annals of Clinical & Laboratory Science 45 (3): 323–326. 
  17. ↑ 17.0 17.1 Suhail, M (2010). "Na, K-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Various Pathophysiological Conditions". Journal of Clinical Medicine Research 2 (1): 1–17. doi:10.4021/jocmr2010.02.263w. PMID 22457695. 
  18. ↑ Patel, S (2016). "Plant-derived cardiac glycosides: Role in heart ailments and cancer management". Biomedicine & Pharmacotherapy 84: 1036–1041. doi:10.1016/j.biopha.2016.10.030. PMID 27780131. 
  19. ↑ 19.0 19.1 Anderson, SE; Barton, CE (2017). "The cardiac glycoside convallatoxin inhibits the growth of colorectal cancer cells in a p53-independent manner". Molecular Genetics and Metabolism Reports 13: 42–45. doi:10.1016/j.ymgmr.2017.07.011. PMID 28819586. 
  20. ↑ 20.0 20.1 Schneider, NF; Geller, FC; Persich, L; Marostica, LL; Pádua, RM; Kreis, W; Braga, FC; Simões, CM (2016). "Inhibition of cell proliferation, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line.". Natural Product Research 30 (11): 1327–1331. doi:10.1080/14786419.2015.1055265. PMID 26252521. https://figshare.com/articles/journal_contribution/1569029. 
  21. ↑ 21.0 21.1 Kaushik, V; Azad, N; Yakisich, JS; Iyer, AKV (2017). "Antitumor effects of naturally occurring cardiac glycosides convallatoxin and peruvoside on human ER+ and triple-negative breast cancers". Cell Death Discovery 3: 17009. doi:10.1038/cddiscovery.2017.9. PMID 28250972. 
  22. ↑ Prassas, I; Diamandis, EP (2008). "Novel therapeutic applications of cardiac glycosides". Nature Reviews Drug Discovery 7 (11): 926–35. doi:10.1038/nrd2682. PMID 18948999. 
  23. ↑ Amarelle, L; Lecuona, E (2018). "The Antiviral Effects of Na,K-ATPase Inhibition: A Minireview". International Journal of Molecular Sciences 19 (8): 2154. doi:10.3390/ijms19082154. PMID 30042322. 
  24. ↑ 24.0 24.1 Cohen, CJ; Williams, JD; Opperman, TJ; Sanchez, R; Lurain, NS; Tortorella, D (2016). "Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication". Journal of Virology 90 (23): 10715–10727. doi:10.1128/JVI.01050-16. PMID 27654292. 
  25. ↑ 25.0 25.1 Gozalpour, E; Greupink, R; Bilos, A; Verweij, V; van den Heuvel, JJ; Masereeuw, R; Russel, FG; Koenderink, JB (2014). "Convallatoxin: a new P-glycoprotein substrate". European Journal of Pharmacology 744: 18–27. doi:10.1016/j.ejphar.2014.09.031. PMID 25264938. 
  26. ↑ Gozalpour, E; Wilmer, MJ; Bilos, A; Masereeuw, R; Russel, FG; Koenderink, JB (2016). "Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays". Toxicology in Vitro 32: 138–145. doi:10.1016/j.tiv.2015.12.009. PMID 26708294. 
  27. ↑ Levrier, C; Kiremire, B; Guéritte, F; Litaudon, M (2012). "Toxicarioside M, a new cytotoxic 10β-hydroxy-19-nor-cardenolide from Antiaris toxicaria". Fitoterapia 83 (4): 660–664. doi:10.1016/j.fitote.2012.02.001. PMID 22348979. 
  28. ↑ Angarskaya, MA; Topchii, LY (1973). "Experimental results relating to the metabolism of the cardiac glycosides". Chemistry of Natural Compounds 9 (5): 621–624. doi:10.1007/BF00564387. 
  29. ↑ Anderson, KE; Bergdahl, B; Bodem, G; Dengler, H; Dutta, S; Foerster, J; Greeff, K; Grosse-Brockhoff, F et al. (2017). Cardiac Glycosides: Part II: Pharmacokinetics and Clinical Pharmacology. Springer Science & Business Media. pp. 73–74. 
  30. ↑ Scheline, RR (1991). Handbook of Mammalian Metabolism of Plant Compounds. CRC Press. 
  31. ↑ 31.0 31.1 Xu, J; Guo, Y; Sui, T; Wang, Q; Zhang, Y; Zhang, R; Wang, M; Guan, S et al. (2017). "Molecular mechanisms of anti-oxidant and anti-aging effects induced by convallatoxin in Caenorhabditis elegans". Free Radical Research 51 (5): 529–544. doi:10.1080/10715762.2017.1331037. PMID 28503972. 
  32. ↑ 32.0 32.1 Fitzgerald, KT (2010). "Lily toxicity in the cat". Topics in Companion Animal Medicine 25 (4): 213–217. doi:10.1053/j.tcam.2010.09.006. PMID 21147474. 



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