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|IUPACName=(3a''S'',4''S'',4a''R'',7a''R'',8''R'',9a''R'')-4-hydroxy-4a,8-<br>dimethyl-3-methylidene-3,3a,4,4a,7a,8,9,9a-<br>octahydroazulenofuran-2,5-dione |
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|Section1= {{Chembox Identifiers |
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| IUPACName=(8α''H'')-6α-Hydroxy-4-oxo-10α-ambrosa-2,11(13)-dieno-12,8-lactone |
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| CASNo=6754-13-8 |
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| SystematicName=(3a''S'',4''S'',4a''R'',7a''R'',8''R'',9a''R'')-4-Hydroxy-4a,8-dimethyl-3-methylidene-3,3a,4,4a,7a,8,9,9a-octahydroazulenofuran-2,5-dione |
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| PubChem=23205 |
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| KEGG=C09473 |
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| SMILES=CC1CC2C(C(C3(C1C=CC3=O)C)O)C(=C)C(=O)O2 |
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| ChEMBL = 338474 |
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| UNII = 4GUY9L896T |
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| ChemSpiderID = 21713 |
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| SMILES = O=C/2O3C(1/C=C\C(=O)1(C)(O)3C\2=C)C |
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| 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 |
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| InChIKey = ZVLOPMNVFLSSAA-XEPQRQSNBI |
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| StdInChI = 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 |
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'''Helenalin''' is a ] with potent ] and ] effects found in '']'' and ''Arnica chamissonis foliosa''. It is the main compound responsible for the therapeutic effects of ''Arnica''. |
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'''Helenalin''', or (-)-4-Hydroxy-4a,8-dimethyl-3,3a,4a,7a,8,9,9a-octahydroazuleno</nowiki>furan-2,5-dione, is a toxic ] which can be found in several plants such as '']'' and '']'' Helenalin is responsible for the toxicity of the ''Arnica'' spp. |
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While it is not completely known how sesquiterpene lactones exert their anti-inflammatory effect, helenalin has been shown to selectively inhibit the ] ], which plays a key role in regulating ], through a unique mechanism.<ref name="pmid9837931">{{cite journal |author=Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I |title=The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65 |journal=J Biol Chem |volume=273 |issue=50 |pages=33508–16 |year=1998 |pmid=9837931 |doi= 10.1074/jbc.273.50.33508|url=http://www.jbc.org/cgi/content/full/273/50/33508}}</ref> '']'', it is also a potent, selective inhibitor of human ]<ref>{{cite journal |author=Huang PR, Yeh YM, Wang TC |title=Potent inhibition of human telomerase by helenalin |journal=Cancer Lett |volume=227 |issue=2 |pages=169–74 |year=2005 |pmid=16112419 |doi=10.1016/j.canlet.2004.11.045}}</ref>—which may partially account for its antitumor effects—has anti-]l activity,<ref name="pmid15856894">{{cite journal |author=Jimenez-Ortiz V, Brengio SD, Giordano O, ''et al.'' |title=The trypanocidal effect of sesquiterpene lactones helenalin and mexicanin on cultured epimastigotes |journal=J Parasitol |volume=91 |issue=1 |pages=170–4 |year=2005 |pmid=15856894 |doi=10.1645/GE-3373}}</ref><ref name="pmid12221603">{{cite journal |author=Schmidt TJ, Brun R, Willuhn G, Khalid SA |title=Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones |journal=Planta Med |volume=68 |issue=8 |pages=750–1 |year=2002 |pmid=12221603 |doi=10.1055/s-2002-33799}}</ref> and is toxic to '']''.<ref name="pmid15022176">{{cite journal |author=François G, Passreiter CM |title=Pseudoguaianolide sesquiterpene lactones with high activities against the human malaria parasite Plasmodium falciparum |journal=Phytother Res |volume=18 |issue=2 |pages=184–6 |year=2004 |pmid=15022176 |doi=10.1002/ptr.1376}}</ref> |
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Although toxic, helenalin possesses some '']'' ] and ] 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.<ref name=Perry /><ref name=Tornhamre>{{cite journal |doi=10.1016/S0006-2952(01)00729-8|title=Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C 4 synthase in human blood cells |journal=Biochemical Pharmacology |volume=62 |issue=7 |pages=903–911 |year=2001 |last1=Tornhamre |first1=Susanne |last2=Schmidt |first2=Thomas J. |last3=Näsman-Glaser |first3=Barbro |last4=Ericsson |first4=Inger |last5=Lindgren |first5=Jan Åke|pmid=11543725 }}</ref> |
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== Structure and reactivity == |
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Animal and ''in vitro'' studies have also suggested that helenalin can reduce the growth of '']'' and reduce the severity of ''S. aureus'' infection.<ref name="pmid17010538">{{cite journal |author=Boulanger D, Brouillette E, Jaspar F, ''et al.'' |title=Helenalin reduces Staphylococcus aureus infection in vitro and in vivo |journal=Vet Microbiol |volume=119 |issue=2–4 |pages=330–8 |year=2007 |pmid=17010538 |doi=10.1016/j.vetmic.2006.08.020}}</ref> |
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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 ].<ref name=Widen>{{cite journal | vauthors = Widen JC, Kempema AM, Baur JW, Skopec HM, Edwards JT, Brown TJ, Brown DA, Meece FA, Harki DA | title = Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles | journal = ChemMedChem | volume = 13 | issue = 4 | pages = 303–311 | date = February 2018 | pmid = 29349898 | pmc = 5894512 | doi = 10.1002/cmdc.201700752 }}</ref><ref name=Zwicker>{{cite journal | vauthors = Zwicker P, Schultze N, Niehs S, Albrecht D, Methling K, Wurster M, Wachlin G, Lalk M, Lindequist U, Haertel B | title = Differential effects of Helenalin, an anti-inflammatory sesquiterpene lactone, on the proteome, metabolome and the oxidative stress response in several immune cell types | journal = Toxicology in Vitro | volume = 40 | pages = 45–54 | date = April 2017 | pmid = 27998807 | doi = 10.1016/j.tiv.2016.12.010 }}</ref> |
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Helenalin is a highly toxic compound, with hepatic and lymphatic tissues particularly vulnerable to its effects.<ref>{{cite journal | last1 = Chapman | first1 = Dennis E. | last2 = Roberts | first2 = G.B. | last3 = Reynolds | first3 = D.J. | last4 = Grippo | first4 = Anne A. | last5 = Holbrook | first5 = David J. | last6 = Hall | first6 = Iris H. | last7 = Chaney | first7 = Stephen G. | last8 = Chang | first8 = J. | last9 = Lee | first9 = K. H. | title = Acute Toxicity of Helenalin in BDF1 Mice | journal = Toxicological Sciences | volume = 10 | pages = 302 | year = 1988 | doi = 10.1093/toxsci/10.2.302 }}</ref> |
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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.<ref name=Tornhamre /> |
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Addition reactions can occur because thiol groups are strong nucleophiles; a thiol has a lone pair of electrons.<ref name=Poole>{{cite journal | vauthors = Poole LB | title = The basics of thiols and cysteines in redox biology and chemistry | journal = Free Radical Biology & Medicine | volume = 80 | pages = 148–57 | date = March 2015 | pmid = 25433365 | pmc = 4355186 | doi = 10.1016/j.freeradbiomed.2014.11.013 }}</ref> |
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== Chemical derivatives == |
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==References== |
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{{Reflist}} |
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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.<ref name=Perry>{{cite journal | vauthors = Perry NB, Burgess EJ, Rodríguez Guitián MA, Romero Franco R, López Mosquera E, Smallfield BM, Joyce NI, Littlejohn RP | title = Sesquiterpene lactones in Arnica montana: helenalin and dihydrohelenalin chemotypes in Spain | journal = Planta Medica | volume = 75 | issue = 6 | pages = 660–6 | date = May 2009 | pmid = 19235681 | doi = 10.1055/s-0029-1185362 }}</ref><ref name=Tornhamre /> |
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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.<ref name=Beekman>{{cite journal | vauthors = Beekman AC, Woerdenbag HJ, van Uden W, Pras N, Konings AW, Wikström HV, Schmidt TJ | title = Structure-cytotoxicity relationships of some helenanolide-type sesquiterpene lactones | journal = Journal of Natural Products | volume = 60 | issue = 3 | pages = 252–7 | date = March 1997 | pmid = 9090867 | doi = 10.1021/np960517h }}</ref> |
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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 Michael addition sites. Poorer accessibility results in a compounds with lower toxicity.{{Citation needed|date=April 2018}} Another possibility is that a derivative lacking one of the reactive groups, such as the cyclopentenone group, may have a lower toxicity.{{Citation needed|date=April 2018}} |
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== Some biochemical effects of helenalin == |
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Helenalin can target the p65 subunit (also called RelA) of the transcription factor ]. It can react with ]38 in RelA by Michael addition. Both reactive groups, α-methylene-γ-butyrolactone and cyclopentene, can react with this cysteine.<ref name=Widen /> It was also found that helenalin can inhibit human ], 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.<ref name=Huang>{{cite journal | vauthors = Huang PR, Yeh YM, Wang TC | title = Potent inhibition of human telomerase by helenalin | journal = Cancer Letters | volume = 227 | issue = 2 | pages = 169–74 | date = September 2005 | pmid = 16112419 | doi = 10.1016/j.canlet.2004.11.045 }}</ref> 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.<ref name=Tornhamre /> |
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== Metabolism == |
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Helenalin inhibits ] 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 ], 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 in cholesterol levels.<ref name=Chapman>{{cite journal | vauthors = Chapman DE, Roberts GB, Reynolds DJ, Grippo AA, Holbrook DJ, Hall IH, Chaney SG, Chang J, Lee KH | title = Acute toxicity of helenalin in BDF1 mice | journal = Fundamental and Applied Toxicology | volume = 10 | issue = 2 | pages = 302–12 | date = February 1988 | pmid = 3356317 | doi = 10.1016/0272-0590(88)90315-6 }}</ref> |
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Helenalin also suppresses essential immune functions, such as those mediated by activated CD4<sup>+</sup> T-cells, by multiple mechanisms.<ref name=Berges>{{cite journal | vauthors = Berges C, Fuchs D, Opelz G, Daniel V, Naujokat C | title = Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms | journal = Molecular Immunology | volume = 46 | issue = 15 | pages = 2892–901 | date = September 2009 | pmid = 19656571 | doi = 10.1016/j.molimm.2009.07.004 }}</ref> |
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== ''In vitro'' anti-inflammatory and anti-neoplastic effects == |
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Helenalin and some of its derivatives have been shown to have potent anti-inflammatory and anti-neoplastic effects '']''. 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<ref name=Tornhamre /><ref name=Huang /><ref name=Hall_1980>{{cite journal | vauthors = Hall IH, Starnes CO, Lee KH, Waddell TG | title = Mode of action of sesquiterpene lactones as anti-inflammatory agents | journal = Journal of Pharmaceutical Sciences | volume = 69 | issue = 5 | pages = 537–43 | date = May 1980 | pmid = 6247478 | doi = 10.1002/jps.2600690516 }}</ref> |
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.<ref name=Lee>{{cite journal | vauthors = Lee KH, Hall IH, Mar EC, Starnes CO, ElGebaly SA, Waddell TG, Hadgraft RI, Ruffner CG, Weidner I | title = Sesquiterpene antitumor agents: inhibitors of cellular metabolism | journal = Science | volume = 196 | issue = 4289 | pages = 533–6 | date = April 1977 | pmid = 191909 | doi = 10.1126/science.191909 | bibcode = 1977Sci...196..533L }}</ref><ref name=Schroeder>{{cite journal | vauthors = Schröder H, Lösche W, Strobach H, Leven W, Willuhn G, Till U, Schrör K | title = Helenalin and 11 alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways | journal = Thrombosis Research | volume = 57 | issue = 6 | pages = 839–45 | date = March 1990 | pmid = 2116680 | doi = 10.1016/0049-3848(90)90151-2 }}</ref> The dose used varied per study. There is currently no ''in vivo'' evidence regarding helenalin's anti-inflammatory and anti-tumour effects, if any. |
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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 than 10%, more research is required whether those remain safe and are more efficient than the current available medications.<ref name=Brito>{{cite journal |doi=10.3109/10582452.2014.883012|title=Systematic Review on the Efficacy of Topical ''Arnica'' montanafor the Treatment of Pain, Swelling and Bruises |journal=Journal of Musculoskeletal Pain |volume=22 |issue=2 |pages=216–223 |year=2014 |last1=Brito|first1=N |last2=Knipschild|first2=P |last3=Doreste-Alonso|first3=J|s2cid=76330596 }}</ref> |
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== Application == |
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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.<ref name=Berges /> Currently helenalin is used topically in homeopathic gels and microemulsions. Helenalin is not ]-approved for medical application.<ref>"U.S. National Library of Medicine," . Available: https://clinicaltrials.gov/ct2/results?cond=&term=arnica+montana&cntry=&state=&city=&dist=. .</ref> |
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== Toxicity == |
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When applied topically on humans, helenalin can cause ] in sensitive individuals. However, it is considered generally safe when applied this way. Oral administration of large doses of helenalin can cause ], ], and ] and ]. 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.<ref name=Hall_1980_2>{{cite journal | vauthors = Hall IH, Lee KH, Starnes CO, Muraoka O, Sumida Y, Waddell TG | title = Antihyperlipidemic activity of sesquiterpene lactones and related compounds | journal = Journal of Pharmaceutical Sciences | volume = 69 | issue = 6 | pages = 694–7 | date = June 1980 | pmid = 7205585 | doi = 10.1002/jps.2600690622 }}</ref><ref name=Witzel>{{cite journal | vauthors = Witzel DA, Ivie W, Dollahite JW | title = Mammalian toxicity of helenalin, the toxic principle of Helenium microcephalum CD (smallhead sneezeweed) | journal = American Journal of Veterinary Research | volume = 37 | issue = 7 | pages = 859–61 | date = July 1976 | pmid = 937811 }}</ref> 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.<ref name=Chapman /> Parenteral administration showed a higher toxic effect when compared to oral administration.<ref>B. H. Rumack, "POISINDEX(R) Information System Micromedex, Inc.", CCIS, vol. 172, 2017.</ref><ref>A. H. Hall and B. H. Rumack, "TOMES(R) Information System Micromedex, Inc." CCIS, vol. 172, 2017</ref> |
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==Pharmacology== |
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{{see also|Arnica montana#Medicinal use}} |
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Helenalin has a variety of observed effects '']'' including ] and ] activities.<ref name="pmid8033301">{{cite journal | vauthors = Powis G, Gallegos A, Abraham RT, Ashendel CL, Zalkow LH, Grindey GB, Bonjouklian R | title = Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues | journal = Cancer Chemotherapy and Pharmacology | volume = 34 | issue = 4 | pages = 344–50 | year = 1994 | pmid = 8033301 | doi = 10.1007/BF00686043 | s2cid = 22818483 }}</ref> Helenalin has been shown to selectively inhibit the ] ], which plays a key role in regulating ], through a unique mechanism.<ref name="pmid9837931">{{cite journal | vauthors = Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I | title = The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 50 | pages = 33508–16 | date = December 1998 | pmid = 9837931 | doi = 10.1074/jbc.273.50.33508 | doi-access =free }}</ref> ''In vitro'', it is also a potent, selective inhibitor of human ]<ref name=Huang />—which may partially account for its antitumor effects—has anti-]l activity,<ref name="pmid15856894">{{cite journal | vauthors = Jimenez-Ortiz V, Brengio SD, Giordano O, Tonn C, Sánchez M, Burgos MH, Sosa MA | title = The trypanocidal effect of sesquiterpene lactones helenalin and mexicanin on cultured epimastigotes | journal = The Journal of Parasitology | volume = 91 | issue = 1 | pages = 170–4 | date = February 2005 | pmid = 15856894 | doi = 10.1645/GE-3373 | s2cid = 42378778 | display-authors = etal }}</ref><ref name="pmid12221603">{{cite journal | vauthors = Schmidt TJ, Brun R, Willuhn G, Khalid SA | title = Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones | journal = Planta Medica | volume = 68 | issue = 8 | pages = 750–1 | date = August 2002 | pmid = 12221603 | doi = 10.1055/s-2002-33799 }}</ref> and is toxic to '']''.<ref name="pmid15022176">{{cite journal | vauthors = François G, Passreiter CM | title = Pseudoguaianolide sesquiterpene lactones with high activities against the human malaria parasite Plasmodium falciparum | journal = Phytotherapy Research | volume = 18 | issue = 2 | pages = 184–6 | date = February 2004 | pmid = 15022176 | doi = 10.1002/ptr.1376 | s2cid = 3048612 }}</ref> |
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Animal and ''in vitro'' studies have also suggested that helenalin can reduce the growth of '']'' and reduce the severity of ''S. aureus'' infection.<ref name="pmid17010538">{{cite journal | vauthors = Boulanger D, Brouillette E, Jaspar F, Malouin F, Mainil J, Bureau F, Lekeux P | title = Helenalin reduces Staphylococcus aureus infection in vitro and in vivo | journal = Veterinary Microbiology | volume = 119 | issue = 2–4 | pages = 330–8 | date = January 2007 | pmid = 17010538 | doi = 10.1016/j.vetmic.2006.08.020 | display-authors = etal }}</ref> |
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== References == |
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