Free accessResearch articleFirst published online 2008-8
Structural Characterization of Genuine (-)-Pipermethystine,(-)-Epoxypipermethystine,(+)-Dihydromethysticin and Yangonin from the Kava Plant ( Piper methysticum )
Two alkaloids, (-)-pipermethystine and (-)-epoxypipermethystine, and two lactones, (+)-dihydromethysticin and yangonin, were isolated from the kava plant (Piper methysticum) and crystallographically authenticated.
StickelF, BaumullerHM, SeitzK, VasilakisD, SeitzG, SeitzHK, SchuppanD. (2003) Hepatitis induced by Kava (Piper methysticum rhizoma). Journal of Hepatology, 39, 62–67.
4.
Centers for Disease Control and Prevention (CDC). (2002) Hepatic toxicity possibly associated with kava-containing products — United States, Germany, and Switzerland, 1999–2002. MMWR Morbidity and Mortal Weekly Reports, 51, 1065–1067.
5.
GowPJ, ConnellyNJ, HillRL, CrowleyP, AngusPW. (2003) Fatal fulminant hepatic failure induced by a natural therapy containing kava. Medical Journal of Australia, 178, 442–443.
6.
RussmannS, BarguilY, CabalionP, KritsanidaM, DuhetD, LauterburgBH. (2003) Hepatic injury due to traditional aqueous extracts of kava root in New Caledonia. European Journal of Gastroenterology & Hepatology, 15, 1033–1036.
7.
CurrieBJ, CloughAR. (2003) Kava hepatotoxicity with Western herbal products: does it occur with traditional kava use?Medical Journal of Australia, 178, 421–422.
8.
JohnsonBM, QiuSX, ZhangS, ZhangF, BurdetteJE, YuL, BoltonJL, van BreemenRB. (2003) Identification of novel electrophilic metabolites of Piper methysticum Forst. (Kava). Chemical Research in Toxicology, 16, 733–740.
9.
ZouL, HarkeyMR, HendersonGL. (2005) Synthesis, in vitro reactivity, and identification of 6-phenyl-3-hexen-2-one in human urine after Kava-Kava (Piper methysticum) ingestion. Planta Medica, 71, 142–146.
10.
WhittonPA, LauA, SalisburyA, WhitehouseJ, EvansCS. (2003) Kava lactones and the kava-kava controversy. Phytochemistry, 64, 673–679.
11.
WeissJ, SauerA, FrankA, UngerM. (2005) Extracts and kavalactones of Piper methysticum G. Forst (kava-kava) inhibit P-glycoprotein in vitro. Drug Metabolism and Disposition, 33, 1580–1583.
12.
MaY, SachdevaK, LiuJ, FordM, YangD, KhanIA, ChichesterCO, YanB. (2004) Desmethoxyyamgonin and dihydromethysticin are two major pharmacological kavalactones with marked activity on the induction of CYP3A23. Drug Metabolism and Disposition, 32, 1317–1324.
13.
ZouL, HarkeyMR, HendersonGL. (2002) Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sciences, 71, 1579–1589.
NerurkarPV, DragullK, TangC.-S. (2004) In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones. Toxicological Sciences, 79, 106–111.
16.
DentaliSJ. (1997) Herb Safety Review Kava - Piper methysticum Forster f. (Piperaceae). Herb Research Foundation, Boulder, CO.
17.
SmithRM. (1979) Pipermethystine, a novel pyridone alkaloid from Piper methysticum. Tetrahedron, 35, 437–439.
18.
SmithRM. (1983) Kava lactones in Piper methysticum from Fiji. Phytochemistry, 22, 1055–1056.
19.
YoshiokaM, DragullK, YoshidaW, TangCS. (2006) Structure-toxicity relationships of kava piperidone alkaloids in human hepatoma cells. 7th Tetrahedron Symposium, Kyoto, Japan. Abstract book, p. 116.
20.
LimST, DragullK, TangCS, BittenbenderHC, EfirdJT, NerurkarPV. (2007) Effects of kava alkaloid, pipermethystine, and kavalactones on oxidative stress and cytochrome P450 in F-344 rats. Toxicological Sciences, 97, 214–221.
21.
EngelP, NowackiW. (1972) Die Molekular- und Kristallstruktur von 4-Methoxy-6-(5′,6′-dioxymethylen-styryl)-5,6-dihydro-α-pyron (Methysticin) C15H14O5. Zeitschrift für Kristallographie, 136, 437–452.
22.
YoshinoA, NowackiW. (1972) The molecular and crystal structure of D,L-4-methoxy-6-styryl-5,6-dihydro-α-pyrone (kavain). Zeitschrift für Kristallographie, 136, 66–80.
23.
EngelP, NowackiW. (1972) Die Molekular- und Kristallstruktur von 4-Methoxy-6-(1′,2′-dihydrostyryl)-5,6-dihydro-α-pyron (Dihydrokavain) C14H16O3. Zeitschrift für Kristallographie, 136, 453–467.
24.
MascarenhasYP, LanaVLP, von BulowMV, GottliebOR. (1973) Crystal data of 5,6-dehydrocavain and derivatives. Acta Crystallographica, B29, 1361–1361.
25.
Additional details on the isolation and crystallographic data are deposited as Supporting Information.
ArrayásRG, AlcudiaA, LiebeskindLS. (2001) Facile enantiodivergent approach to 5-hydroxy-5,6-dihydro-2(1H)-pyridones. First total synthesis of both entantiomers of pipermethystine. Organic Letters, 3, 3381–3383.
28.
SnatzkeG, HänselR. (1968) Die absolutkonfiguration der Kawa-lactone. Tetrahedron Letters, 9, 1797–1799.
29.
The C6a–C7a/C6′–C7′, C7a–C8a/C7′–C8′ and C8a–C9a/C8′–C9′ pairs of bond distances were restrained to 1.50±0.01 Å and the C6a·C··8a/C6′···C8′ and C7a···C9a/C7′···C9′ interactions to 2.45±0.01 Å. The O1a–C6a and O1a–C6′ bond distances were restrained to within 0.01 Å of each other, as were the C4a–C6a/C4a–C6′, C6a–C7a/C6′–C7′, O4a–C11a/O4a–C11′ and O5a–C12a/O5a–C12′ pairs. Additionally, the temperature factors of the primed atoms were set to those of the unprimed (b) atoms; the vibrations of the C6a, C7a and C8a atoms were restrained to be nearly isotropic. The C8a, C9a, C10a, C11a, C12a, C13a and C14a atoms were restrained to lie in an almost flat plane, as were the primed C8′, C9′, C10′, C11′, C12′, C13′ and C14′ atoms. The phenyl/phenylene rings were refined as rigid hexagons on 1.39 Å sides; hydrogen atoms were included in the refinement in the riding model approximation.
