Biotransformation of 1,4-Cineole,a Monoterpene Ether

1.The metabolism of 1,4-cineole, a monoterpene ether, was studied in the rabbit.

2.Four neutral and one acidic metabolites were isolated from the urine and shown to be 9-hydroxy-1,4-cineole, 3,8-dihydroxy-1,4-cineole, 8,9-dihydroxy-1,4-cineole, 1,4-cineole-8-en-9-ol and 1,4-cineole-9-carboxylic acid.     

Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1,4-cineole, a monoterpene cyclic ether, by rat and human liver microsomes.

1. Oxidation of 1,4-cineole, a monoterpene cyclic ether, was studied in rat and human liver microsomes and recombinant cytochrome P450 (P450 or CYP) enzymes expressed in insect cells in which human P450 and NADPH-P450 reductase cDNAs have been introduced. On analysis with gas chromatography/mass spectrometry, 2-exo-hydroxy-1,4-cineole was identified as a principal oxidation product of 1,4-cineole catalysed by rat and human P450 enzymes. 2. CYP3A4 was a major enzyme involved in the 2-hydroxylation of 1,4-cineole by human liver microsomes, based on the following lines of evidence. First, 1,4-cineole 2-hydroxylation activities catalysed by human liver microsomes were inhibited by ketoconazole, a potent inhibitor of CYP3A activities, and an anti-CYP3A4 antibody. Second, there was a good correlation beteeen CYP3A4 contents and 1,4-cineole 2-hydroxylation activities in liver microsomes of eighteen human samples examined. Finally, of 10 recombinant human P450 enzymes examined, CYP3A4 had the highest activity for 1,4-cineole 2-hydroxylation. 3. Liver microsomal 1,4-cineole 2-hydroxylation activities were induced in rat by pregnenolone 16alpha-carbonitrile and dexamethasone and extensively inhibited by ketoconazole, indicative of the possible roles of CYP3A enzymes in this reaction. 4. Kinetic analysis showed that Vmax/Km for 1,4-cineole 2-hydroxylation catalysed by liver microsomes was higher in a human sample HL-104 (4.6 microM(-1) min(-1)) than those of rat treated with pregnenolone 16alpha-carbonitrile (0.49 microM(-1) min(-1)) and dexamethasone (0.36 microM(-1) min(-1)). 5. 1,8-Cineole, a structurally related monoterpene previously shown to be catalysed by CYP3A enzymes, inhibited 1,4-cineole 2-hydroxylation catalysed by human liver microsomes, whereas 1,4-cineole did not inhibit 1,8-cineole 2-hydroxylation activities. Both compounds caused inhibition of testosterone 6beta-hydroxylation by human liver microsomes, the former compound being more inhibitory than the latter. 6. These results suggest that 1,4-cineole and 1,8-cineole, two plant essential oils present in Citrus medica L. var. acida and Eucalyptus polybractea, respectively, are converted to 2-hydroxylated products by CYP3A enzymes in rat and human liver microsomes. It is unknown at present whether the 2-hydroxylation products of these compounds are more active biologically than the parent compound.     

Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1,4-cineole,a monoterpene cyclic ether,by rat and human liver microsomes

1. Oxidation of 1,4-cineole, a monoterpene cyclic ether, was studied in rat and human liver microsomes and recombinant cytochrome P450 (P450 or CYP) enzymes expressed in insect cells in which human P450 and NADPH-P450 reductase cDNAs have been introduced. On analysis with gas chromatography/mass spectrometry, 2- exo -hydroxy-1,4-cineole was identified as a principal oxidation product of 1,4-cineole catalysed by rat and human P450 enzymes. 2. CYP3A4 was a major enzyme involved in the 2-hydroxylation of 1,4-cineole by human liver microsomes, based on the following lines of evidence. First, 1,4-cineole 2-hydroxylation activities catalysed by human liver microsomes were inhibited by ketoconazole, a potent inhibitor of CYP3A activities, and an anti-CYP3A4 antibody. Second, there was a good correlation between CYP3A4 contents and 1,4-cineole 2-hydroxylation activities in liver microsomes of eighteen human samples examined. Finally, of 10 recombinant human P450 enzymes examined, CYP3A4 had the highest activity for 1,4-cineole 2-hydroxylation. 3. Liver microsomal 1,4-cineole 2-hydroxylation activities were induced in rat by pregnenolone 16 α-carbonitrile and dexamethasone and extensively inhibited by ketoconazole, indicative of the possible roles of CYP3A enzymes in this reaction. 4. Kinetic analysis showed that V max / K m for 1,4-cineole 2-hydroxylation catalysed by liver microsomes was higher in a human sample HL-104 (4.6 μM -1?min -1) than those of rat treated with pregnenolone 16 α-carbonitrile (0.49 μM -1?min -1) and dexamethasone (0.36 μM -1?min -1). 5. 1,8-Cineole, a structurally related monoterpene previously shown to be catalysed by CYP3A enzymes, inhibited 1,4-cineole 2-hydroxylation catalysed by human liver microsomes, whereas 1,4-cineole did not inhibit 1,8-cineole 2-hydroxylation activities. Both compounds caused inhibition of testosterone 6 β -hydroxylation by human liver microsomes, the former compound being more inhibitory than the latter. 6. These results suggest that 1,4-cineole and 1,8-cineole, two plant essential oils present in Citrus medica L. var. acida and Eucalyptus polybractea, respectively, are converted to 2-hydroxylated products by CYP3A enzymes in rat and human liver microsomes. It is unknown at present whether the 2-hydroxylation products of these compounds are more active biologically than the parent compound.     

氯可托龙新戊酸酯及其有关物质的结构鉴定

目的对氯可托龙新戊酸酯及其原料药中有关物质进行分离及结构鉴定。方法采用制备高效液相色谱法对氯可托龙新戊酸酯中的杂质进行分离,并应用HPLC-ESI-MS、NMR、UV、IR法对氯可托龙新戊酸酯及其有关物质进行结构鉴定。结果氯可托龙新戊酸酯原料药中含有(6R,9R,16R)-9-氯-6β-氟-11β,21-二羟基-16α-甲基-1,4-孕甾二烯-3,20-二酮-21-新戊酸酯[(6R,9R,16R)-9-chloro-6β-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate,1]、(9R,16R)-9-氯-4-氟-11β,21-二羟基-16α-甲基-1,4-孕甾二烯-3,20-二酮-21-新戊酸酯[(9R,16R)-9-chloro-4-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate,2]和(9R,16R)-9-氯-6α-氟-11β,21-二羟基-16α-甲基-1,4-孕甾二烯-3,20-二酮-11,21-二新戊酸酯[(9R,16R)-9-chloro-6α-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-11,21-dipivalate,3]3种杂质。结论从氯可托龙新戊酸酯原料药中分离得到3个杂质,3个化合物均为首次发现。其中杂质1为6-H的差向异构体,杂质2为同分异构体,杂质3为11-OH与新戊酸酯化产物。结合合成过程分析,三者可能均为合成过程中的副产物。     

Anxiolytic-like effect of the monoterpene 1,4-cineole in mice

Recent studies have shown that some monoterpenes exert anxiolytic- and depressant-like actions, however, these effects from monoterpene 1,4-cineole are still unknown. This work aimed to study the effects of 1,4-cineole in classic animal models for depression- and anxiety-like behavior, specifically the elevated plus maze (EPM), hole board, open field, pentobarbital sleeping time, forced swimming, tail suspension and rota rod tests. 1,4-Cineole was administered orally to mice (100, 200 and 400 mg/kg), while diazepam (1 or 2 mg/kg) and imipramine (10 or 30 mg/kg) were used as standard drugs. 1,4-Cineole (400 mg/kg) modified all parameters observed in the EPM, while no significant variation was observed on general motor activity in the open-field test. In the hole-board assay, 1,4-cineole induced increase on the number of head dips. Forced swimming and tail suspension tests showed that cineole (200 and/or 400 mg/kg) was able to promote significant increase on the immobility time, while a decreased sleep latency was observed (200 and 400 mg/kg ) on the pentobarbital sleeping time. Cineole had no effect on the motor coordination of animals in the rota rod test. The results suggest that 1,4-cineole presents potential anxiolytic-like action consistent with possible general depression of the CNS.     

2,3—双（烷胺甲基）—1,4—二羟基蒽醌的合成及抗肿瘤活性

在1,4-二羟基蒽醌的2,3位上,引入烷胺甲基侧链,合成了6个新化合物。另合成在2位引入烷胺甲基,3位为甲基的新化合物9个。大多数化合物在体内外呈现较微弱的抗肿瘤活性。     

Note New Naphthoquinones from Plumbago zeylanica

From the roots of Plumbago zeylanica, two new naphthoquinones, 3,8-dihydroxy-6-methoxy-2-iso-propyl-1,4-naphthoquinone and 5,7-dihydroxy-8-methoxy-2-methyl-1,4-naphthoquinone, have been isolated and their structures established on the basis of chemical and spectral studies.     

Untersuchung an 1,4-Naphthochinonen, 18. Mitt.: 6-Methyl- und 3,6-Dimethylplumbagin

1,4-Naphthoquinones, XVIII: 6-Methyl- and 3,6-Dimethylplumbagin 3,6-Dimethylplumbagin ( 12 ) results from the radical methylation of 6-methyl-plumbagin ( 9 ). The precursor of 9 is 1,5-dihydroxy-2,6-dimethylnaphthalene ( 7 ), the key reaction is the bis-ortho lithiation of 1,5-bis-methoxymethoxynaphthalene ( 3 ). In the course of the oxidation of 7 ← 9 by O₂ activated by Cosalen® the dimethyl derivative 10 of the natural compound maritinone is prepared as a byproduct.     

巴戟天和恩施巴戟的蒽醌化合物

从巴戟天(Morinda officinalis How.)根的氯仿提取物中,分离得八个蒽醌化合物,其中二个为新化合物,它们的结构为1,6-二羟基-2,4-二甲氧基蒽醌(1,6-dihydroxy-2,4-dimethoxyanthraquinone,V),1,6-二羟基-2-甲氧基蒽醌(1,6-dihydroxy-2-methoxy-anthraquinone,Ⅵ)。从恩施巴戟(Damnacanthus indicus Linn.)根的氯仿提取物中,分离得七个蒽醌化合物,其中一个为新化合物,其结构为1,4-二甲氧基-2α-羟基蒽醌(1,4-dimethoxy-2-hydroxyanthraquinone,ⅩⅢ)。     

Effect of fluorosteroids on drug response and metabolism.

In female rats, zoxazolamine paralysis was significantly reduced by pretreatment with pregnenolone-16α-carbonitrile (PCN), spironolactone, dexamethasone acetate, betamethasonc acetate, 9α-fluoro-11 β,21-dihydroxy-16α, 17α-dimethyl-1,4-pregnadiene-3,20-dione, 6α-fluoro-9α-chloro-11 β-acetoxy-21-valeryloxy-16α-methyl-1,4-pregnadiene-3, 9α-fluorocortisol acetate, triamcinolone or adrenocorticotropic hormone (ACTH). With the exception of triamcinolone and ACTH. the protective effects of these compounds were associated with decreased drug concentrations in plasma at the end of the pharmacologic response, compared with controls killed at the same time. The drug levels were found to be lowered via hepatic drug-metabolizing enzyme induction. All the fluorosteroids exerted glucocorticoid activity. Thus, PCN and spironolactone protect via increased drug metabolism, triamcinolone and ACTH via decreased organ sensitivity, and the remaining fluorosteroids via both prophylactic mechanisms.     

Phase II trial of mitoxantrone in head and neck cancer

Summary Mitoxantrone (1,4-dihydroxy-5,8-bis((2-[(2-hydroxyethyl)amino]ethyl)amino)-9, 10 anthracenedione dihydrochloride, NSC 301,739) is a new aminoanthraquinone derivative with clinical activity in the treatment of advanced breast cancer (1, 2), lymphoma (3), and acute leukemia (4). We have carried out a phase II trial of mitoxantrone using an every three weeks dosing schedule in patients with advanced head and neck cancers.     

Identification of unknown impurities in triamcinolone acetonide palmitate

In the present study, we analyzed the structures of the two unknown impurities that were contained more than 0.1% in triamcinolone acetonide palmitate by using HPLC-DAD and HPLC-MS hyphenated techniques, and these impurities were synthesized and purified by column chromatography. Based on the results of NMR spectroscopy, IR spectroscopy, and MS, the two impurities were confirmed as 9-fluoro-11β,21-dihydroxy-16α,17-(isopropylidenedioxy)pregna-1,4-diene-3,20-dione 21-myristate and stearate, respectively.     

Interactions between novel terpenes and main components of rat and human skin: mechanistic view for transdermal delivery of propranolol hydrochloride

The purpose of this study was to investigate the effectiveness and mechanism(s) of percutaneous absorption of propranolol hydrochloride (PHCL) across rat and human cadaver skin using seven novel terpenes with reference to marker terpene 1,8-cineole. In-vitro skin permeation studies were carried out via rat and human skin models. The mechanism of skin permeation of PHCL by terpenes was evaluated by FTIR, DSC, activation energy measurement and histopathological examination. Amongst the new terpenes, 1,4-cineole was found to be most effective enhancer for diffusion of PHCL through rat skin (ER=3.07) and human cadaver skin (ER=2.42) as compared to control. FTIR spectra and DSC thermogram of skin treated with aforesaid terpenes indicated that permeation occurred due to the disruption of lipid bilayers. No apparent skin irritation (erythema, edema) was observed on treatment of skin with terpenes, the irritation was higher with the β-citronellene and rose oxide. It was concluded that 1,4-cineole can be successfully used as potential permeation enhancer for PHCL. It enhanced the absorption of hydrophilic drug by extraction and disruption of lipid bilayers and keratin denaturation of stratum corneum.     

Inhibitory effects of glycosides from the leaves of Melaleuca quinquenervia on vascular contraction of rats

Two new glycosides, 3-hydroxy-5-methoxy-4-methylphenyl beta-D-glucopyranoside (1) and 4-benzoyl-2-C-beta-glucopyranosyl-3,5-dihydroxy-6-methylphenyl beta-D-glucopyranoside (2), together with four known glycosides, 2-endo-beta-D-glucopyranosyloxy-1,8-cineole (3a), 2-exo-beta-D-glucopyranosyloxy-1,8-cineole (3b), roseoside (4), and citroside A (5), were isolated from the methanolic extract of leaves of Melaleuca quinquenervia. Their structures were elucidated on the basis of spectroscopic analysis. Compounds 1, 2a and 3 inhibited contractile response induced by phenylephrine in aortic rings from Sprague-Dawley rats. This inhibition was independent of the endothelium. Compounds 2 and 4 significantly relaxed precontracted aortic rings, in an endothelium-dependent manner. Pretreatment of N(omega)-nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor, partially attenuated the vasorelaxation induced by both compounds, suggesting that nitric oxide was likely the responsible mediator. The rank-order potency (EC 50 value) of vasorelaxing activities of these compounds is 4 > 2 > 2a > 3 > 1.     

1,4,5,8-四甲氧基萘-2-甲醛的合成

对紫草素合成中间体1,4,5,8-四甲氧基萘-2-甲醛的制备工艺进行了改进,由萘茜在溴化四丁基铵催化下进行还原甲基化的收率由文献报道的44%提高到90%,标题化合物总收率72%(以对二甲氧基苯计).     

Ether derivatives of 3-amino-1,2-propanediols, VI. Syntheses and pharmacological investigations of 5,8-bis-[2-hydroxy-3-(alkylamino)propoxy]-1,4-dihydronaphthalenes

By reaction of 5,8-dihydroxy-1,4-dihydronaphthalene ( 1 ) with epichlorohydrine 5,8-bis-(2,3-epoxypropoxy)-1,4-dihydronaphthalene ( 2 ) was synthesized. Aminolysis of 2 led to the 3-amino-1,2-propanediols 3-13 . Pharmacological screening showed hypotensive and β-adrenoceptor blocking activities, as well as low toxicity.     

Triterpenes and xanthones from the stem bark of Garcinia tetralata

A new compound, 3β,18,19β-trihydroxylupane, was isolated from Garcinia tetralata, along with five known compounds, garcinexanthone B, morolic acid acetate, toxyloxanthone A, 6,11-dihydroxy-2,2-dimethylpyrano[3,2-c]xanthen-7(2H)-one, and 1,4-dihydroxy-5,6-dimethoxy-xanthone. The structure of the new compound was established by extensive spectroscopic techniques.     

Photochemical decomposition of alkannin/shikonin enantiomers

Alkannin/shikonin ((±)-5,8-dihydroxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinone), isolated from Macrotomia euchroma, is sensitive to light exposure. A chloroform solution of alkannin/shikonin was exposed to sunlight for 1 month. The major photolytic product, a newly discovered naphthoquinone derivative, was isolated by adsorption chromatography. The chemical structure of the purified photolytic product was identified by NMR, MS and FTIR techniques to be (−)-5,8-dihydroxy-2-(1-hydroxy-3-oxo-4-methyl-4-pentenyl)-1,4-naphthoquinone, indicating that a photo-oxidation reaction had occurred.     

Kinetic study of the percutaneous absorption of 1,2,4-3H-labelled flupamesone.

Two different creams containing 4,4'-methylene bis-[(9 alpha-fluor-11 beta,21-dihydroxy-16alpha,17alpha-isopropylidenedioxy-1,4-pregnadiene-3,20-dione)-3-methoxy-2-naphthoate] (flupamesone) and triamcinolone-acetonide, both labelled with tritium, were prepared in order to study their absorption kinetics. Results were compared in order to find structure-activity relations following Malkinson's hypothesis. The radioactivity was measured in samples of skin taken at various intervals of time after the application of the cream. The results showed a reservoir of corticoids at 400--700 mu depth and that flupamesone remains longer in skin than does triamcinolone-acetonide.     

New compounds from the seeds of Embelia ribes Burm

Phytochemical investigation of the seeds of Embelia ribes Burm. resulted in the isolation of three new compounds identified as 3-(4"-hydroxyoctadecanyloxy)-p-quinonyl-5-methylene-8-(10-pentanyloxy)-p-quinone (embelinol) (1), n-pentacosanyl-n-nonadeca-7'-en-9'-alpha-ol-1'-oate (embeliaribyl ester) (2) and 1,2,4,5-tetrahydroxy 3-undecanyl benzene (embeliol) (3) along with the known compound 2,5-dihydroxy-3-undecyl-2,5-cyclohexadiene-1,4-dione (embelin) (4). Their structures have been established on the basis of spectral data analyses and chemical reactions.