Helenalin

Helenalin
Names
Preferred IUPAC name
(3aS,4S,4aR,7aR,8R,9aR)-4-Hydroxy-4a,8-dimethyl-3-methylidene-3,3a,4,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
InChI
  • InChI=1S/C15H18O4/c1-7-6-10-12(8(2)14(18)19-10)13(17)15(3)9(7)4-5-11(15)16/h4-5,7,9-10,12-13,17H,2,6H2,1,3H3/t7-,9+,10-,12-,13+,15+/m1/s1 ☒N
    Key: ZVLOPMNVFLSSAA-XEPQRQSNSA-N ☒N
  • InChI=1/C15H18O4/c1-7-6-10-12(8(2)14(18)19-10)13(17)15(3)9(7)4-5-11(15)16/h4-5,7,9-10,12-13,17H,2,6H2,1,3H3/t7-,9+,10-,12-,13+,15+/m1/s1
    Key: ZVLOPMNVFLSSAA-XEPQRQSNBI
SMILES
  • O=C/2O[C@@H]3C[C@H]([C@@H]1/C=C\C(=O)[C@@]1(C)[C@@H](O)[C@@H]3C\2=C)C
Properties
Chemical formula
 C15H18O4
Molar mass 262.305 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

Helenalin, or (-)-4-Hydroxy-4a,8-dimethyl-3,3a,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione, is a toxic sesquiterpene lactone which can be found in several plants such as Arnica montana and Arnica chamissonis subsp. foliosa. Helenalin is responsible for the toxicity of the Arnica spp. Although toxic, helenalin possesses some in vitro anti-inflammatory and anti-neoplastic effects. Helenalin can inhibit certain enzymes, such as 5-lipoxygenase and leukotriene C4 synthase. For this reason the compound or its derivatives may have potential medical applications.[1][2]

Structure and reactivity

Helenalin belongs to the group of sesquiterpene lactones which are characterised by a lactone ring. Beside this ring, the structure of helenalin has two reactive groups (α-methylene-γ-butyrolactone and a cyclopentenone group) that can undergo a Michael addition.[3][4] The double bond in the carbonyl group can undergo a Michael addition with a thiol group, also called a sulfhydryl group. Therefore, helenalin can interact with proteins by forming covalent bonds to the thiol groups of cysteine-containing proteins/peptides, such as glutathione. This effect can disrupt the molecule's biological function.[2] Addition reactions can occur because thiol groups are strong nucleophiles; a thiol has a lone pair of electrons.[5]

Chemical derivatives

There are several derivatives of helenaline known within the same sesquiterpene lactone group; pseudoguaianolides. Most of these derivatives occur naturally, such as the compound dihydrohelenalin, but there are also some semi-synthetic derivatives known, such as 2β-(S-glutathionyl)-2,3-dihydrohelenalin.[1][2] In general, most derivatives are more toxic than helenalin itself. Among these, derivatives with the shortest ester groups are most likely to contain a higher toxicity.[6] Other derivatives include 11α,13-dihydrohelenalin acetate, 2,3-dehydrohelenalin and 6-O-isobutyrylhelenalin. The molecular conformation differs between helenalin and its derivatives, which affects the lipophilicity and the accessibility of the Micheal addition sites. Poorer accessibility results in a compounds with lower toxicity. Another possibility is that a derivative lacking one of the reactive groups, such as the cyclopentenone group, may have a lower toxicity.

Some biochemical effects of helenalin

Helenalin can target the p65 subunit (also called RelA) of the transcription factor NF-κB. It can react with Cys38 in RelA by Michael addition. Both reactive groups, α-methylene-γ-butyrolactone and cyclopentene, can react with this cysteine.[3] It was also found that helenalin can inhibit human telomerase, a ribonucleoprotein complex, by Michael addition. In this case also, both reactive groups of helenalin can interact with the thiol group of a cysteine and inhibit the telomerase activity.[7] Helenalin inhibits the formation of leukotrienes in human blood cells by inhibiting LTC4 synthase activity. Helenalin reacts with its cyclopentenone ring to the thiol group of the synthase.[2]

Metabolism

Helenalin inhibits cytochrome P450 enzymes by reacting with thiol groups, resulting in inhibition of the mixed-function oxidase system. These effects are important for the cytotoxicity of helenalin. The levels of glutathione, which contains sulfhydryl groups, are reduced in helenaline-treated cells, further increasing the toxicity of helenalin. Depending on the dose of helenalin, thiol-bearing compounds such as glutathione may provide some protection to cells from helenalin toxicity. It was also seen that helenalin increase CPK and LDH activities in serum and that it inhibits multiple enzymes of the liver involved in triglyceride synthesis. Therefore, helenaline causes acute liver toxicity, accompanied by a decrease cholesterol levels.[8]

Helenalin also suppresses essential immune functions, such as those mediated by activated CD4+ T-cells, by multiple mechanisms.[9]

In vitro anti-inflammatory and anti-neoplastic effects

Helenalin and some of its derivatives have been shown to have potent anti-inflammatory and anti-neoplastic effects in vitro. Some studies have suggested that the inhibition by helenalin of platelet leukotriene C4 synthase, telomerase activity and transcription factor NF-κB contributes to helenalin's in vitro anti-inflammatory and anti-neoplastic activity[2][7][10] .[11][12] The dose used varied per study. There is currently no in vivo evidence regarding helenalin's anti-inflammatory and anti-tumour effects, if any. The efficacy of helenalin for treatment of pain and swelling, when applied topically, is not supported by the current available evidence at doses of 10% or lower. For doses higher that 10%, more research is required whether those remain safe and are more efficient than the current available medications.[13]

Application

In former times, plant extracts containing helenalin were used as a herbal medicine for the treatment of sprains, blood clots, muscle strain and rheumatic complaints.[9] Currently helenalin is used topically in homeopathic gels and microemulsions. Helenalin is not FDA-approved for medical application.[14]

Toxicity

When applied topically on humans, helenalin can cause contact dermatitis in sensitive individuals. However, it is considered generally safe when applied this way. Oral administration of large doses of helenalin can cause gastroenteritis, muscle paralysis, and cardiac and liver damage. The toxicity of helenalin was studied in mammalian species such as mice, rat, rabbit and sheep, where the oral LD50 of helenalin was established between 85 and 150 mg/kg.[15][16] It was shown in a mouse model that helenalin caused reduced levels of cholesterol. In a rat model, alcohol hepatic injury was prevented by helenalin administration.[8][17] Parenteral administration showed a higher toxic effect when compared to oral administration.[18][19]

Pharmacology

Helenalin has a variety of observed effects in vitro including anti-inflammatory and antitumour activities.[20] Helenalin has been shown to selectively inhibit the transcription factor NF-κB, which plays a key role in regulating immune response, through a unique mechanism.[21] In vitro, it is also a potent, selective inhibitor of human telomerase[7]—which may partially account for its antitumor effects—has anti-trypanosomal activity,[22][23] and is toxic to Plasmodium falciparum.[24]

Animal and in vitro studies have also suggested that helenalin can reduce the growth of Staphylococcus aureus and reduce the severity of S. aureus infection.[25]

References

  1. 1 2 Perry NB, Burgess EJ, Rodríguez Guitián MA, Romero Franco R, López Mosquera E, Smallfield BM, Joyce NI, Littlejohn RP (May 2009). "Sesquiterpene lactones in Arnica montana: helenalin and dihydrohelenalin chemotypes in Spain". Planta Medica. 75 (6): 660–6. doi:10.1055/s-0029-1185362. PMID 19235681.
  2. 1 2 3 4 5 Tornhamre, Susanne; Schmidt, Thomas J.; Näsman-Glaser, Barbro; Ericsson, Inger; Lindgren, Jan Åke (2001). "Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C 4 synthase in human blood cells". Biochemical Pharmacology. 62 (7): 903–911. doi:10.1016/S0006-2952(01)00729-8. PMID 11543725.
  3. 1 2 Widen JC, Kempema AM, Baur JW, Skopec HM, Edwards JT, Brown TJ, Brown DA, Meece FA, Harki DA (February 2018). "Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles". ChemMedChem. 13 (4): 303–311. doi:10.1002/cmdc.201700752. PMC 5894512. PMID 29349898.
  4. ↑ Zwicker P, Schultze N, Niehs S, Albrecht D, Methling K, Wurster M, Wachlin G, Lalk M, Lindequist U, Haertel B (April 2017). "Differential effects of Helenalin, an anti-inflammatory sesquiterpene lactone, on the proteome, metabolome and the oxidative stress response in several immune cell types". Toxicology in Vitro. 40: 45–54. doi:10.1016/j.tiv.2016.12.010. PMID 27998807.
  5. ↑ Poole LB (March 2015). "The basics of thiols and cysteines in redox biology and chemistry". Free Radical Biology & Medicine. 80: 148–57. doi:10.1016/j.freeradbiomed.2014.11.013. PMC 4355186. PMID 25433365.
  6. ↑ Beekman AC, Woerdenbag HJ, van Uden W, Pras N, Konings AW, Wikström HV, Schmidt TJ (March 1997). "Structure-cytotoxicity relationships of some helenanolide-type sesquiterpene lactones". Journal of Natural Products. 60 (3): 252–7. doi:10.1021/np960517h. PMID 9090867.
  7. 1 2 3 Huang PR, Yeh YM, Wang TC (September 2005). "Potent inhibition of human telomerase by helenalin". Cancer Letters. 227 (2): 169–74. doi:10.1016/j.canlet.2004.11.045. PMID 16112419.
  8. 1 2 Chapman DE, Roberts GB, Reynolds DJ, Grippo AA, Holbrook DJ, Hall IH, Chaney SG, Chang J, Lee KH (February 1988). "Acute toxicity of helenalin in BDF1 mice". Fundamental and Applied Toxicology. 10 (2): 302–12. doi:10.1016/0272-0590(88)90315-6. PMID 3356317.
  9. 1 2 Berges C, Fuchs D, Opelz G, Daniel V, Naujokat C (September 2009). "Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms". Molecular Immunology. 46 (15): 2892–901. doi:10.1016/j.molimm.2009.07.004. PMID 19656571.
  10. ↑ Hall IH, Starnes CO, Lee KH, Waddell TG (May 1980). "Mode of action of sesquiterpene lactones as anti-inflammatory agents". Journal of Pharmaceutical Sciences. 69 (5): 537–43. doi:10.1002/jps.2600690516. PMID 6247478.
  11. ↑ Lee KH, Hall IH, Mar EC, Starnes CO, ElGebaly SA, Waddell TG, Hadgraft RI, Ruffner CG, Weidner I (April 1977). "Sesquiterpene antitumor agents: inhibitors of cellular metabolism". Science. 196 (4289): 533–6. Bibcode:1977Sci...196..533L. doi:10.1126/science.191909. PMID 191909.
  12. ↑ Schröder H, Lösche W, Strobach H, Leven W, Willuhn G, Till U, Schrör K (March 1990). "Helenalin and 11 alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways". Thrombosis Research. 57 (6): 839–45. doi:10.1016/0049-3848(90)90151-2. PMID 2116680.
  13. ↑ Brito, N; Knipschild, P; Doreste-Alonso, J (2014). "Systematic Review on the Efficacy of Topical Arnica montanafor the Treatment of Pain, Swelling and Bruises". Journal of Musculoskeletal Pain. 22 (2): 216–223. doi:10.3109/10582452.2014.883012. S2CID 76330596.
  14. ↑ "U.S. National Library of Medicine," [Online]. Available: https://clinicaltrials.gov/ct2/results?cond=&term=arnica+montana&cntry=&state=&city=&dist=. [Accessed 8 March 2018].
  15. ↑ Hall IH, Lee KH, Starnes CO, Muraoka O, Sumida Y, Waddell TG (June 1980). "Antihyperlipidemic activity of sesquiterpene lactones and related compounds". Journal of Pharmaceutical Sciences. 69 (6): 694–7. doi:10.1002/jps.2600690622. PMID 7205585.
  16. ↑ Witzel DA, Ivie W, Dollahite JW (July 1976). "Mammalian toxicity of helenalin, the toxic principle of Helenium microcephalum CD (smallhead sneezeweed)". American Journal of Veterinary Research. 37 (7): 859–61. PMID 937811.
  17. ↑ Lin X, Zhang S, Huang R, Wei L, Tan S, Liang S, Tian Y, Wu X, Lu Z, Huang Q (June 2014). "Helenalin attenuates alcohol-induced hepatic fibrosis by enhancing ethanol metabolism, inhibiting oxidative stress and suppressing HSC activation". Fitoterapia. 95: 203–13. doi:10.1016/j.fitote.2014.03.020. PMID 24704336.
  18. ↑ B. H. Rumack, "POISINDEX(R) Information System Micromedex, Inc.", CCIS, vol. 172, 2017.
  19. ↑ A. H. Hall and B. H. Rumack, "TOMES(R) Information System Micromedex, Inc." CCIS, vol. 172, 2017
  20. ↑ Powis G, Gallegos A, Abraham RT, Ashendel CL, Zalkow LH, Grindey GB, Bonjouklian R (1994). "Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues". Cancer Chemotherapy and Pharmacology. 34 (4): 344–50. doi:10.1007/BF00686043. PMID 8033301. S2CID 22818483.
  21. ↑ Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I (December 1998). "The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65". The Journal of Biological Chemistry. 273 (50): 33508–16. doi:10.1074/jbc.273.50.33508. PMID 9837931.
  22. ↑ Jimenez-Ortiz V, Brengio SD, Giordano O, Tonn C, Sánchez M, Burgos MH, Sosa MA, et al. (February 2005). "The trypanocidal effect of sesquiterpene lactones helenalin and mexicanin on cultured epimastigotes". The Journal of Parasitology. 91 (1): 170–4. doi:10.1645/GE-3373. PMID 15856894. S2CID 42378778.
  23. ↑ Schmidt TJ, Brun R, Willuhn G, Khalid SA (August 2002). "Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones". Planta Medica. 68 (8): 750–1. doi:10.1055/s-2002-33799. PMID 12221603.
  24. ↑ François G, Passreiter CM (February 2004). "Pseudoguaianolide sesquiterpene lactones with high activities against the human malaria parasite Plasmodium falciparum". Phytotherapy Research. 18 (2): 184–6. doi:10.1002/ptr.1376. PMID 15022176. S2CID 3048612.
  25. ↑ Boulanger D, Brouillette E, Jaspar F, Malouin F, Mainil J, Bureau F, Lekeux P, et al. (January 2007). "Helenalin reduces Staphylococcus aureus infection in vitro and in vivo". Veterinary Microbiology. 119 (2–4): 330–8. doi:10.1016/j.vetmic.2006.08.020. PMID 17010538.
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