(R)-Terpinen-4-ol was mixed in an artificial diet at a concentration of 1 mg/g of diet, and the diet was fed to the last instar larvae of common cutworm (Spodoptera litura). Metabolites were recovered from frass and analyzed spectroscopically. (R)-Terpinen-4-ol was transformed mainly to (R)-p-menth-1-en-4,7-diol. Similarly, (S)-terpinen-4-ol was transformed mainly to (S)-p-menth-1-en-4,7-diol. The C-7 position (allylic methyl group) of (R)- and (S)-terpinen-4-ol was preferentially oxidized.
We examined the in vitro metabolism of (+)-terpinen-4-ol by human liver microsomes and recombinant enzymes. The biotransformation of (+)-terpinen-4-ol was investigated by gas chromatography-mass spectrometry (GC-MS). (+)-Terpinen-4-ol was found to be oxidized to (+)-(1R,2S,4S)-1,2-epoxy-p-menthan-4-ol, (+)-(1S,2R,4S)-1,2-epoxy-p-menthan-4-ol, and (4S)-p-menth-1-en-4,8-diol by human liver microsomal P450 enzymes. The identities of (+)-terpinen-4-ol metabolites were determined through the relative abundance of mass fragments and retention times on GC-MS. Of 11 recombinant human P450 enzymes tested, CYP1A2, CYP2A6, and CYP3A4 were found to catalyze the oxidation of (+)-terpinen-4-ol. Based on several lines of evidence, CYP2A6 and CYP3A4 were determined to be major enzymes involved in the oxidation of (+)-terpinen-4-ol by human liver microsomes. First, of the 11 recombinant human P450 enzymes tested, CYP1A2, CYP2A6 and CYP3A4 catalyzed oxidation of (+)-terpinen-4-ol. Second, oxidation of (+)-terpinen-4-ol was inhibited by (+)-menthofuran and ketoconazole, inhibitors known to be specific for these enzymes. Finally, there was a good correlation between CYP2A6 and CYP3A4 activities and (+)-terpinen-4-ol oxidation activities in the 10 human liver microsomes.
IDENTIFICATION AND USE: 1-Terpinen-4-ol is colorless to pale yellow liquid with pine odor. It is found in more than 200 derivatives from leaves, herbs, and flowers. It is used in artificial geranium and pepper oils and in perfumery for creating herbaceous and lavender notes. It is also used as experimental medication and topical antimicrobial. HUMAN EXPOSURE AND TOXICITY: Terpinen-4-ol can induce human leukemic MOLT-4 cell apoptosis via both intrinsic and extrinsic pathways. It suppress the production of superoxide by monocytes, but not neutrophils, suggesting the potential for selective regulation of cell types by these components during inflammation. In addition, the water-soluble components of tea tree oil can suppress pro-inflammatory mediator production by activated human monocytes. ANIMAL STUDIES: Oral LD50's range from 1.0 to 4.3 g/kg in rodents. A single study of dermal toxicity in rabbits reported a LD50 of >3 g/kg.
This study compared the antimicrobial activity of Melaleuca alternifolia (tea tree) oil with that of some of its components, both individually and in two-component combinations. Minimum inhibitory concentration and time-kill assays revealed that terpinen-4-ol, the principal active component of tea tree oil, was more active on its own than when present in tea tree oil. Combinations of terpinen-4-ol and either gamma-terpinene or p-cymene produced similar activities to tea tree oil. Concentration-dependent reductions in terpinen-4-ol activity and solubility also occurred in the presence of gamma-terpinene. Non-oxygenated terpenes in tea tree oil appear to reduce terpinen-4-ol efficacy by lowering its aqueous solubility. These findings explain why tea tree oil can be less active in vitro than terpinen-4-ol alone and further suggest that the presence of a non-aqueous phase in tea tree oil formulations may limit the microbial availability of its active components.
Terpinen-4-ol (4TRP) is a monoterpenoid alcoholic component of essential oils obtained from several aromatic plants. We investigated the psychopharmacological and electrophysiological activities of 4TRP in male Swiss mice and Wistar rats. 4TRP was administered intraperitoneally (i.p.) at doses of 25 to 200 mg/kg and intracerebroventricularly (i.c.v.) at concentrations of 10, 20, and 40 ng/2 uL. For in vitro experiments, 4TRP concentrations were 0.1mM and 1.0mM. 4TRP (i.p.) inhibited pentylenetetrazol- (PTZ-) induced seizures, indicating anticonvulsant effects. Electroencephalographic recordings showed that 4TRP (i.c.v.) protected against PTZ-induced seizures, corroborating the behavioural results. To determine whether 4TRP exerts anticonvulsant effects via regulation of GABAergic neurotransmission, we measured convulsions induced by 3-mercapto-propionic acid (3-MP). The obtained results showed involvement of the GABAergic system in the anticonvulsant action exerted by 4TRP, but flumazenil, a selective antagonist of the benzodiazepine site of the GABAA receptor, did not reverse the anticonvulsant effect, demonstrating that 4TRP does not bind to the benzodiazepine-binding site. Furthermore, 4TRP decreased the sodium current through voltage-dependent sodium channels, and thus its anticonvulsant effect may be related to changes in neuronal excitability because of modulation of these channels.
Artemisia phaeolepis, a perennial herb with a strong volatile odor, grows on the grasslands of Mediterranean region. Essential oil obtained from Artemisia phaeolepis was analyzed by gas chromatography-flame ionization detection and gas chromatography-mass spectrometry. A total of 79 components representing 98.19% of the total oil were identified, and the main compounds in the oil were found to be eucalyptol (11.30%), camphor (8.21%), terpine-4-ol (7.32%), germacrene D (6.39), caryophyllene oxide (6.34%), and caryophyllene (5.37%). The essential oil showed definite inhibitory activity against 10 strains of test microorganisms. Eucalyptol, camphor, terpine-4-ol, caryophyllene, germacrene D and caryophyllene oxide were also examined as the major components of the oil. Camphor showed the strongest antimicrobial activity; terpine-4-ol, eucalyptol, caryophyllene and germacrene D were moderately active and caryophyllene oxide was weakly active. The study revealed that the antimicrobial properties of the essential oil can be attributed to the synergistic effects of its diverse major and minor components.
The combined effect of terpinen-4-ol, the main component of tea tree oil, and capric acid against mycelial growth of Candida albicans and murine oral candidiasis was evaluated in vitro and in vivo. Mycelial growth of C. albicans was estimated by the Cristal violet method. Combination of these compounds revealed a potent synergistic inhibition of growth. Therapeutic efficacy of the combination was evaluated microbiologically in murine oral candidiasis, and its application of the compounds clearly demonstrated therapeutic activity. Based on these results, the combined agent of terpinen-4-ol and capric acid was discussed as a possible candidate for oral candidiasis therapy.
The terpenes disturb lipid arrangement in the intercellular region of the stratum corneum (SC) that leads to the increased permeability of the skin. This effect is used in technology of transdermal drug forms and depends on physicochemical properties of terpenes and their amounts penetrated to the stratum corneum; however terpenes do not need penetrate into viable skin tissue and this event is not even desired. To correlate skin absorption and elimination kinetics of four cyclic terpenes, namely alpha-pinene, beta-pinene, eucalyptol and terpinen-4-ol, applied as neat substance with their physicochemical properties. The terpenes were applied onto the human skin in vitro, and after 1-4 h their content in the separated by a tape-stripping method stratum corneum layers and in the epidermis/dermis was determined using GC. Similarly, the amounts of terpenes in the skin were analysed during 4 h following 1 h absorption. The fastest and progressive penetration into all skin layers was observed for terpinen-4-ol. All studied terpenes are absorbed in the viable epidermis/dermis, however penetration into this layers is time-dependent process, constantly increasing during 4 h. Like for stratum corneum, the largest cumulation in epidermis/dermis was observed for terpinen-4-ol. The elimination of terpenes from the stratum corneum was fast, especially in deeper layers, and much faster if the initial cumulation was small. Investigated cyclic terpenes represent different penetration and elimination characteristics and do not permeate across the skin to the acceptor medium due to large cumulation in the skin tissue. The penetration of terpenes into stratum corneum is greater if their log P-value is close to 3.
The purpose of this study was to evaluate the in vitro cutaneous penetration of five terpenes--linalool, linalyl acetate, terpinen-4-ol, citronellol and alpha-pinene--applied in pure essential oils or in dermatological formulations (o/w emulsion, oily solution or hydrogel) containing 0.75 % w/w of the essential oils. Different skin absorption was observed depending on the type of the vehicle and terpenes' log P values. Cutaneous accumulation of terpenes is several times higher when they are applied in pure essential oils than in topical vehicles. Penetration of terpinen-4-ol to the skin was better from an oily solution (approximately 90 ug/cm (2)) than from an emulsion (60 ug/cm (2)). No penetration of linalyl acetate from topical vehicles into viable skin was observed, but also for this terpene penetration to the upper layers of the stratum corneum was 2-times higher when an oily solution was used. In contrast, the cutaneous absorption of linalool was the same from both vehicles (50-60 ug/cm (2)). The skin penetration of alpha-pinene was not traceable when it was applied in an oily solution. Only a small amount (approximately 5 ug/cm (2)) of this terpene was determined in viable skin after application as a hydrogel. Citronellol applied in a hydrogel penetrated into all skin layers in a total amount of 25 ug/cm (2), while no penetration into viable skin layers after application of an oily solution was noted. Only citronellol permeated into the acceptor medium.
This work aimed to evaluate the effect induced by excipients conventionally used for topical dosage forms, namely isopropyl myristate (IPM) or oleic acid (OA) or polyethylene glycol 400 (PEG400) or Transcutol (TR), on the human skin permeability of terpinen-4-ol (T4OL) contained in the pure Tea tree oil. The effect of such excipients was determined by evaluating the absorption of T4OL using human epidermis and the perturbation of the organization of stratum corneum by ATR-FTIR. Among the tested excipients OA enhanced the absorption of T4OL by perturbing the stratum corneum lipid barrier. Other excipients caused a weak enhancement effect and their use should be carefully monitored.
The purpose of this study was to investigate dermal pharmacokinetics of terpinen-4-ol in rats following topical administration of plai oil derived from the rhizomes of Zingiber cassumunar Roxb. Unbound terpinen-4-ol concentrations in dermal tissue were measured by microdialysis. The dermal pharmacokinetic study of terpinen-4-ol was performed under non-occlusive conditions. The oil was topically applied at a dose of 2, 4, and 8 mg/square cm plai oil corresponding to the amount of 1.0, 1.9, and 3.8 mg/square cm terpinen-4-ol, respectively. Following topical application of the oil, terpinen-4-ol rapidly distributed into the dermis and demonstrated linear pharmacokinetics with no changes in the dose-normalized area under the concentration-time curves across the investigated dosage range. The mean percentages of free terpinen-4-ol distributed in the dermis per amount of administered were 0.39 +/- 0.06 %, 0.41 +/- 0.08 %, and 0.30 +/- 0.03 % for 2, 4, and 8 mg/square cm doses, respectively. The dermal pharmacokinetics of terpinen-4-ol could provide information for its further formulation development and therapy schedules.
The biotransformations of (RS)-linalool (1), (S)-citronellal (2), and sabinene (3) with fungi isolated from the epicarp of fruits of Citrus genus of the Amazonian forest (i.e., C. limon, C. aurantifolia, C. aurantium, and C. paradisiaca) are reported. The more active strains have been characterized, and they belong to the genus Penicillium and Fusarium. Different biotransformation products have been
Fe‐Catalyzed Anaerobic Mukaiyama‐Type Hydration of Alkenes using Nitroarenes
作者：Anup Bhunia、Klaus Bergander、Constantin Gabriel Daniliuc、Armido Studer
DOI：10.1002/anie.202015740
日期：2021.4.6
Hydration of alkenes using first row transitionmetals (Fe, Co, Mn) under oxygen atmosphere (Mukaiyama‐type hydration) is highly practical for alkene functionalization in complex synthesis. Different hydration protocols have been developed, however, control of the stereoselectivity remains a challenge. Herein, highly diastereoselective Fe‐catalyzed anaerobic Markovnikov‐selective hydration of alkenes
carbonate and much less reactive methyl carbamates with primary (1°), secondary (2°), and tertiary (3°) alcohols was established with the use of a lanthanum(III) complex, which was prepared in situ from lanthanum(III) isopropoxide (3 mol %) and 2-(2-methoxyethoxy)ethanol (6 mol %). In particular, corresponding carbonates and carbamates obtained were of synthetic utility from the viewpoint of the selective protection
Cyclic Bent Allene Hydrido-Carbonyl Complexes of Ruthenium: Highly Active Catalysts for Hydrogenation of Olefins
作者：Conor Pranckevicius、Louie Fan、Douglas W. Stephan
DOI：10.1021/jacs.5b02203
日期：2015.4.29
found to be among the most active hydrogenation catalysts, achieving comparable activity to Crabtree's catalyst in the hydrogenation of unactivated trisubstituted olefins and superior activity in the hydrogenation of styrene derivatives in side-by-side catalytic runs. RuH(OSO2CF3)(CO)(SIMes)(CBA) was also found to be highly active in olefinselectivehydrogenation in the presence of a variety of unsaturated
Disclosed are methods and compositions for regulating the melanin content of mammalian melanocytes; regulating pigmentation in mammalian skin, hair, wool or fur; treating or preventing various skin and proliferative disorders; by administration of various compounds, including alcohols, diols and/or triols and their analogues.
