60761-00-4Relevant academic research and scientific papers
Syntheses of chiral 1,8-cineole metabolites and determination of their enantiomeric composition in human urine after ingestion of 1,8-cineole- containing capsules
Schaffarczyk, Monika,Balaban, Teodor Silviu,Rychlik, Michael,Buettner, Andrea
, p. 77 - 85 (2013/06/27)
The chiral metabolites in human urine were investigated after ingestion of a 1,8-cineole (eucalyptol)-containing enterocoated capsule (Soledum). For identification of the various enantiomers the enantiomerically pure (-/+)-α2-hydroxy-1,8- cineole, (-/+)-β2-hydroxy-1,8-cineole, (-/+)-9-hydroxy-1,8-cineole, and (-/+)-2-oxo-1,8-cineole were prepared. To achievethis aim, after acetylation of the synthesized racemic 2-and 9-hydroxy-1,8-cineoles, pig liver esterase- or yeast-mediated hydrolysis provided the (-)-alcohols with their antipodal(+)-acetates with enantiomeric excess of 33-100 %. Dess-Martin periodinane oxidation of the alcohol (+)-α2-hydroxy-1,8-cineole, obtained by hydrolysis of the resolved acetate, provided the corresponding (+)-2-oxo-1,8-cineole, meanwhile the oxidation of (-)-α2-hydroxy-1,8-cineole gave (-)-2-oxo-1,8-cineole. Using these standards seven metabolites (+/-)-α2-hydroxy-1,8-cineole, (+/-)-β2-hydroxy-1,8-cineole, (+/-)-α3-hydroxycineole,(+/-)-3-oxo-1, 8-cineole, 4-hydroxy-1,8-cineole, 7-hydroxy-1,8-cineole, and (+/-)-9-hydroxy-1,8-cineole, all liberated from their glucuronides, were identified in urine by GCMS on a chiral stationary phase after consumption of 10 mg of 1,8-cineole. Metabolite screening using 2H3-1,8- cineol as the internal standard revealed (+/-)-α2-hydroxy-1,8-cineole as the predominant metabolite followed by (+/-)-9-hydroxy-1,8-cineole. Furthermore, the results showed that one enantiomer is always formed preferentially.
An in vivo cytochrome P450cin (CYP176A1) catalytic system for metabolite production
Slessor, Kate E.,Hawkes, David B.,Farlow, Anthony,Pearson, Andrew G.,Stok, Jeanette E.,De Voss, James J.
body text, p. 15 - 20 (2012/07/14)
Cytochrome P450cin (CYP176A1) is a bacterial P450 isolated from Citrobacter braakii that catalyses the hydroxylation of 1,8-cineole to (1R)-6β-hydroxycineole. P450cin uses two redox partners in vitro for catalysis: cindoxin, its physiological FMN-containing redox partner, and Escherichia coli flavodoxin reductase. Here we report the construction of a tricistronic plasmid that expresses P450cin, cindoxin and E. coli flavodoxin reductase and a bicistronic plasmid that encodes only P450 cin and cindoxin. E. coli transformed with the bicistronic vector effectively catalysed the oxidation of 1,8-cineole, with the endogenous E. coli flavodoxin reductase presumably acting as the terminal electron transfer protein. This in vivo system was capable of producing enantiomerically pure (1R)-6β-hydroxycineole in yields of ～1 g/L culture, thus providing a simple, one-step synthesis of this compound. In addition, the metabolism of (1R)- and (1S)-camphor, structural homologues of 1,8-cineole was also evaluated in order to investigate the ability of this in vivo system to produce compounds for mechanistic studies. Significant quantities of five of the six possible secondary alcohols arising from methylene oxidation of both (1R)- and (1S)-camphor were isolated and structurally characterised. The similarity of the (1R)- and (1S)-camphor product profiles highlight the importance of the inherent reactivity of the substrate in determining the regiochemistry of oxidation in the absence of any specific enzyme-substrate binding interactions.
Cineole biodegradation: Molecular cloning, expression and characterisation of (1R)-6β-hydroxycineole dehydrogenase from Citrobacter braakii
Slessor, Kate E.,Stok, Jeanette E.,Cavaignac, Sonia M.,Hawkes, David B.,Ghasemi, Younes,De Voss, James J.
experimental part, p. 81 - 86 (2010/05/17)
The first steps in the biodegradation of 1,8-cineole involve the introduction of an alcohol and its subsequent oxidation to a ketone. In Citrobacter braakii, cytochrome P450cin has previously been demonstrated to perform the first oxidation to produce (1R)-6β-hydroxycineole. In this study, we have cloned cinD from C. braakii and expressed the gene product, which displays significant homology to a number of short-chain alcohol dehydrogenases. It was demonstrated that the gene product of cinD exhibits (1R)-6β-hydroxycineole dehydrogenase activity, the second step in the degradation of 1,8-cineole. All four isomers of 6-hydroxycineole were examined but only (1R)-6β-hydroxycineole was converted to (1R)-6-ketocineole. The (1R)-6β-hydroxycineole dehydrogenase exhibited a strict requirement for NAD(H), with no reaction observed in the presence of NADP(H). The enzyme also catalyses the reverse reaction, reducing (1R)-6-ketocineole to (1R)-6β-hydroxycineole. During this study the N-terminal His-tag used to assist protein purification was found to interfere with NAD(H) binding and lower enzyme activity. This could be recovered by the addition of Ni2+ ions or proteolytic removal of the His-tag.
Enantiomeric purity and odor characteristics of 2- and 3-acetoxy-1,8- cineoles in the rhizomes of Alpinia galanga Willd.
Kubota, Kikue,Someya, Yuki,Yoshida, Reiko,Kobayashi, Akio,Morita, Tetsu-Ichiro,Koshino, Hiroyuki
, p. 685 - 689 (2007/10/03)
(S)-(+)-O-methylmandelate esters of trans- and cis-1,3,3-trimethyl-2- oxabicyclo[2.2.2]octan-5- and 6-ols (2- and 3-hydroxy-1,8-cineoles) were prepared, and eight diastereomers were separated. The absolute configuration of the asymmetric carbons of the cineole moiety of each diastereomer was determined by 1H NMR data according to the Mosher theory. Each mandelate was reduced with LiAlH4 to obtain optically pure hydroxy-1,8-cineoles, this being followed by acetylation to afford optically pure acetoxy-1,8-cineoles. These acetates were subjected to chiral GC, using a cyclodextrin column, and the enantiomeric purity of trans- and cis-1,3,3-trimethyl-2- oxabicyclo[2.2.2]octan-5-and 6-yl acetates in the aroma concentrate from the rhizomes of Alpinia galanga was determined as 93.9 (5S), 19.4 (5R), 63.5 (6R), and 100 (6R) % ee, respectively. The aroma character of each enantiomer was also evaluated by GC-sniffing.
Chiral 2α,4-dihydroxy-1,8-cineole as a possum urinary metabolite
Carman, Raymond M.,Rayner, Anthony C.
, p. 1 - 6 (2007/10/03)
Both enantiomers of 2α,4-dihydroxy-1,8-cineole (2) have been synthesized. The enantiomer present in possum urine is the (-)-(1R,2R,4R)-isomer (2′). This diol is biosynthesized in the possum from (1R,2R,4S)-2α-hydroxy-1,8-cineole (18).
BITRANSFORMATION OF 1,8--CINEOLE BY CULTURED CELLS OF EUCALYPTUS PERRINIANA
Orihara, Yutaka,Furuya, Tsutomu
, p. 641 - 644 (2007/10/02)
Four new biotransformation products, (1R,2R,4S)-1,8-epoxy-p-menthan-2-yl O-β-D-glucopyranoside, (1S,3R,4R)- and (1R,3S,4S)-1,8-epoxy-p-menthan-3-yl O-β-D-glucopyranosides, and (1S,2S,4R)-1,8-epoxy-p-menthan-2-yl O-β-D-glucopyranosyl-(1-->6)-β-D-glucopyranoside, together with a known (1S,2S,4R)-1,8-epoxy-p-menthan-2-yl O-β-D-glucopyranoside were isolated from a cell suspension culture of Eucalyptus perriniana following administration of 1,8-cineole.
ELECTROPHILIC CYCLIZATION OF α-TERPINEOL IN THE PRESENCE OF THALLIUM(III) TRIFLUOROACETATE
Ratner, V. V.,Tregubova, I. N.,Belyaeva, M. G.,Arbuzov, B. A.
, p. 1645 - 1646 (2007/10/02)
Thallium(III) trifluoroacetate in ether causes the cyclization of α-terpineol to give (+/-)-4α-hydroxypinol as the major product. (+/-)-4β-Hydroxypinol and 2-hydroxy-1,8-cineole were also found in slight amounts.
STEROEPECIFIC HYDROXYLATION OF 1,8-CINEOLE USING A MICROBIAL BIOCATALYST
Liu, Wei Guo,Rosazza, John P. N.
, p. 2833 - 2836 (2007/10/02)
The new bacterial catalyst, Bacillus cereus hydroxylates 1,8-cineole (1) to give 6R-exo-hydroxy-1,8-cineole, , (3).The regio- and stereochemical outcome of this reaction was predicted using a model for the B. cereus hydroxylase.
PREPARATION OF BIOLOGICALLY ACTIVE SUBSTANCES AND ANIMAL AND MICROBIAL METABOLITES FROM MENTHOLS, CINEOLES AND KAURANES
Asakawa, Yoshinori,Matsuda, Reiko,Tori, Motoo,Hashimoto, Toshihiro
, p. 3861 - 3870 (2007/10/02)
Six monoterpenoids, l-menthol, l-menthyl acetate, iso-menthol, neo-menthol, 1,4-cineole and 1,8-cineole and one diterpene hydrocarbon, ent-kaurene were oxidized by meta-chloroperbenzoic acid or dry ozone to give various hydroxylated products and their structures elucidated by NMR spectroscopy.Some hydroxylated menthols showed plant growth inhibitory and strong mosquito repellent activity.Among the hydroxylated cineoles, microbial and animal metabolites of cineoles were included.From ent-kauranes, a plant growth inhibitory diterpene alcohol, (-)-16α-hydroxy kaurane was obtained along with 16α-kauran-13α-ol.
Halogenated Terpenoids. XXIV The Bromocineoles
Carman, Raymond M.,Fletcher, Mary T.
, p. 1723 - 1738 (2007/10/02)
The bromination of cineole under a range of conditions is reported.Various bromocineoles and their properties are discussed.
