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We are continuing to study the biotransformation of secondary metabolites such as terpenoids and aromatic compounds from crude drugs and liverworts by microorganisms [1][2][3][4][5][6][7] and mammals 8,9) to obtain some functional substances such as pheromones and aromatics. We reported the biotransformation of sesquiterpenoids such as dehydrocostuslactone, costunolide, a-, b-, and g-cyclocostunolides, asantonin, and atractylon from crude drugs, and an amber constituent, (Ϫ)-ambrox by microorganisms such as Aspergillus niger.10) It has been clarified that a grapefruit essential oil containing nootkatone (1) decreases the somatic fat ratio 11) and its demand by cosmetic and fiber manufacturers has increased. Recently, we have found that the commercially available and cheap aromatic valencene (2) from Valencia orange oil is very efficiently converted into the expensive grapefruit aromatic, nootkatone (1) by biotransformations using Chlorella sp.12) and Mucor sp. 13) In continuation of the biotransformation of the chemical constituents isolated from crude drugs into biologically active compounds, the biotransformations of nootkatone (1) and valencene (2) were examined using Aspergillus niger, Fusarium culmorum, and Botryosphaeria dothidea. This paper deals with the structural elucidation of metabolites of 1 and 2 converted by the three fungi.Biotransformation of Nootkatone (1) by Aspergillus niger A. niger was inoculated and cultivated in a rotary (100 rpm) in Czapek-pepton medium (pH 7.0) at 30°C for 7 d. (ϩ)-Nootkatone (1) (80 mg/200 ml) was added to the medium and further cultivated for 7 d. The crude metabolites obtained from the culture broth by EtOAc extraction were chromatographed on silica gel (n-hexane-EtOAc gradient) to give two metabolites, 12-hydroxy-11,12-dihydronootkatone (3) (10.6%, isolated yield) and C-11 stereomixtures of 11,12-dihydroxy-11,12-dihydronootkatone (nootkatone-11,12-diol) (4, 5) (51.5% isolated yield), respectively.Compound ( Compound 3 showed correlations between (i) H-12/C-7, C-11, and C-13; and (ii) H-13/C-7, C-11 and C-12 in the HMBC spectrum. On the basis of the above spectral data and careful analysis of its 2D NMR spectrum, the structure of metabolite 3 was established to be 12-hydroxy-11,12-dihydronootkatone. The relative configuration at C-11 remained to be clarified.The HR-EI-MS of nootkatone-11,12-diol (a mixture of 4 and 5) showed a peak for [M ϩ ] at m/z 252.1730, indicating the molecular formula of C 15 H 24 O 3 . The FT-IR spectrum of the mixture indicated the presence of a hydroxyl (3358 cm Ϫ1 ) and a conjugated ketone (1652 cm Ϫ1 ) group. The 1 H-and 13 C-NMR spectra showed that 4 and 5 were a mixture of stereoisomers at C-11, the isolation of which was very difficult by any separation method. The structure of 11,12-diol was confirmed by the formation of a methyl ketone (6) on oxidation with NaIO 4 . Treatment of the mixture (4, 5) with 1,1Ј-thiocarbonyldiimidazole gave the thiocarbonates 7 and 8, which were easily separated by HPLC in the ratio of 3 : 2. Teresa ...
We are continuing to study the biotransformation of secondary metabolites such as terpenoids and aromatic compounds from crude drugs and liverworts by microorganisms [1][2][3][4][5][6][7] and mammals 8,9) to obtain some functional substances such as pheromones and aromatics. We reported the biotransformation of sesquiterpenoids such as dehydrocostuslactone, costunolide, a-, b-, and g-cyclocostunolides, asantonin, and atractylon from crude drugs, and an amber constituent, (Ϫ)-ambrox by microorganisms such as Aspergillus niger.10) It has been clarified that a grapefruit essential oil containing nootkatone (1) decreases the somatic fat ratio 11) and its demand by cosmetic and fiber manufacturers has increased. Recently, we have found that the commercially available and cheap aromatic valencene (2) from Valencia orange oil is very efficiently converted into the expensive grapefruit aromatic, nootkatone (1) by biotransformations using Chlorella sp.12) and Mucor sp. 13) In continuation of the biotransformation of the chemical constituents isolated from crude drugs into biologically active compounds, the biotransformations of nootkatone (1) and valencene (2) were examined using Aspergillus niger, Fusarium culmorum, and Botryosphaeria dothidea. This paper deals with the structural elucidation of metabolites of 1 and 2 converted by the three fungi.Biotransformation of Nootkatone (1) by Aspergillus niger A. niger was inoculated and cultivated in a rotary (100 rpm) in Czapek-pepton medium (pH 7.0) at 30°C for 7 d. (ϩ)-Nootkatone (1) (80 mg/200 ml) was added to the medium and further cultivated for 7 d. The crude metabolites obtained from the culture broth by EtOAc extraction were chromatographed on silica gel (n-hexane-EtOAc gradient) to give two metabolites, 12-hydroxy-11,12-dihydronootkatone (3) (10.6%, isolated yield) and C-11 stereomixtures of 11,12-dihydroxy-11,12-dihydronootkatone (nootkatone-11,12-diol) (4, 5) (51.5% isolated yield), respectively.Compound ( Compound 3 showed correlations between (i) H-12/C-7, C-11, and C-13; and (ii) H-13/C-7, C-11 and C-12 in the HMBC spectrum. On the basis of the above spectral data and careful analysis of its 2D NMR spectrum, the structure of metabolite 3 was established to be 12-hydroxy-11,12-dihydronootkatone. The relative configuration at C-11 remained to be clarified.The HR-EI-MS of nootkatone-11,12-diol (a mixture of 4 and 5) showed a peak for [M ϩ ] at m/z 252.1730, indicating the molecular formula of C 15 H 24 O 3 . The FT-IR spectrum of the mixture indicated the presence of a hydroxyl (3358 cm Ϫ1 ) and a conjugated ketone (1652 cm Ϫ1 ) group. The 1 H-and 13 C-NMR spectra showed that 4 and 5 were a mixture of stereoisomers at C-11, the isolation of which was very difficult by any separation method. The structure of 11,12-diol was confirmed by the formation of a methyl ketone (6) on oxidation with NaIO 4 . Treatment of the mixture (4, 5) with 1,1Ј-thiocarbonyldiimidazole gave the thiocarbonates 7 and 8, which were easily separated by HPLC in the ratio of 3 : 2. Teresa ...
Nootkatone (2), the most important and expensive aromatic of grapefruit, decreases the somatic fat ratio, and thus its demand is increasing in the cosmetic and fiber sectors. A sesquiterpene hydrocarbon, (؉)-valencene (1), which is cheaply obtained from Valencia orange, was biotransformed by the green algae Chlorella species and fungi such as Mucor species, Botryosphaeria dothidea, and Botryodiplodia theobromae to afford nootkatone (2) in high yield.Key words nootkatone; valencene; biotransformation; Chlorella; Mucor Microorganisms are able to transform a huge variety of organic compounds, such as terpene hydrocarbons, alkaloids, steroids, antibiotics, and amino acids. 1) We are continuing to study the biotransformation of secondary metabolites such as terpenoids and aromatic compounds from crude drugs and spore-forming green plants by microorganisms [2][3][4][5][6][7][8] and mammals 9,10) to obtain functional substances such as pheromones and perfumes. Recently, it has been clarified that nootkatone (2), the most important grapefruit aromatic, decreases the somatic fat ratio, 11) and therefore its efficient production has been demanded by the cosmetic and fiber industrial sectors. Previously, valencene (1) from the essential oil of Valencia oranges was converted into nootkatone (2) by biotransformation using Enterobacter sp. in only 12% yield, 12) Rodococcus KSM-5706 in 0.5% yield with a complex mixture, 13) and using cytochrome P450 in 20% yield with other complex products.14) Nootkatone (2) was chemically synthesized from valencene (1) Botryosphaeria dothide, and Botryodiplodia theobromae. Little attention has been paid to the biotransformation of terpenoids and aromatic compounds using the green algae Chlorella species. Chlorella fusca var. vacuolata IAMC-28 was inoculated and cultivated while stationary under illumination in Noro medium (pH 8.0) at 25°C for 7 d. (ϩ)-Valencene (1) (20 mg/50 ml) was added to the medium and biotransformed by C. fusca for a further 18 d to afford nootkatone (2) (GC-MS peak area: 89%; isolated yield: 63%). The GC-MS spectrum of the crude metabolites obtained from the culture broth by ether extraction is shown in Fig. 1. The reduction of 2 with NaBH 4 and CeCl 3 gave 2a-hydroxyvalencene (3) in 87% yield, followed by Mitsunobu reaction with p-nitrobenzoic acid, triphenylphosphine, and diethyl azodicarboxylate to give nootkatol (2b-hydroxyvalencene) (4) in 42% yield, which has calcium-antagonistic activity. 17)Compounds 3 and 4 were easily biotransformed by C. fusca and Chlorella pyrenoidosa for only 1 d to give nootkatone (2) in good yield (80-90%), respectively. The biotransformation of compound 1 was further performed by C. pyrenoidosa and Chlorella vulgaris to afford nootkatone in good yield, as shown in Table 1. In the time course (Fig. 2) of the biotransformation of 1 by C. pyrenoidosa, the yield of nootkatone (2) and nootkatol (4) without 2a-hydroxyvalencene (3) increased with the decrease in that of 1, and subsequently the yield of 2 increased with decrease in that of 3. I...
We continue to study the biotransformation of terpenoids and aromatic compounds from crude drugs, liverworts and animal origin by microorganisms [1][2][3][4][5][6][7][8] and mammals 9,10) to obtain functional substances such as pheromones, aromas, and insecticides. Recently, we succeeded in highly efficient production of nootkatone, the most important and expensive grapefruit aroma that decreases somatic fat ratio 11) from the cheap and commercially available valencane-type sesquiterpene hydrocarbon valencene (3) from the valencia orange oil, by biotransformation using Chlorella and Mucor species. 12-14)The structure of aristolane-type sesquiterpene, (ϩ)-1(10)-aristolene (ϭb-gurjunene) (1) 15) whose structure resembles that of nootkatone (4) except for the presence of a 1,1-dimethylcyclopropane ring in the molecule, 1(10)-aristolen-2-one (5) 16,17) possessing excellent citrus scent and anti-microbial activity, and 9a-hydroxy-1(10)-aristolen-2-one (ϭde-bilon) (6) 18,19) having cytotoxic activity were isolated from Nardostachys chinensis. (Ϫ)-Aristolone (7) 20) and 1(10)-aristolen-12-al (9), 21) which inhibit melanin synthesis, 22,23) were also isolated from Aristolochia debilis, while the enantiomer (8) of 7 was obtained from the liverworts Porella caespitans var. setigera 24,25) and Reboulia hemisphaerica. 26)We have previously reported the distribution of a number of novel terpenoids and aromatic compounds possessing biological activities such as antimicrobial, antitumor, and neural sprouting activities. 24,25) 2,3-Secoaromadendrane-type sesquiterpenoids such as plagiochilide (2) and plagiochiline A (10), which are distributed only in liverworts Plagiochila species, also possess a 1,1-dimethylcyclopropane ring. 24,25) Plagiochilide (2) elicits a nerve cell degeneration reparation activity, 27) and plagiochiline A (10) displays strong pungent tasting, intensive insect antifeedant and piscicidal acitivities. 24,25) To obtain more biologically active compounds than the original aristolanes and 2,3-secoaromadendranes, biotransformation of (ϩ)-1(10)-aristolene (1) and plagiochilide (2) by Chlorella fusca var. vacuolata, Mucor species, and Aspergillus niger was examined. This paper deals with the structure elucidation of metabolites obtained by biotransformation of 1 and 2 by these three microorganisms and their Yamashiro-cho, Tokushima 770-8514, Japan. Received January 30, 2006; accepted March 13, 2006 Biotransformation of the aristolane-type sesquiterpene hydrocarbon (؉)-1(10)-aristolene (1) from the crude drug Nardostachys chinensis and of the 2,3-secoaromadendrane-type sesquiterpene lactone plagiochilide (2) from the liverwort Plagiochila fruticosa by three microorganisms, Chlorella fusca var. vacuolata, Mucor species, and Aspergillus niger was investigated. C. fusca var. vacuolata and Mucor sp. introduced oxygen function into the cyclohexane ring of aristolene while A. niger oxidized stereoselectively one methyl of the 1,1-dimethyl group on the cyclopropane ring of aristolanes and 2,3-secoaromadendrane to gi...
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