Syntheses and odor of "bulky group"-modified sandalwood odorants: isophorono-beta-santalol analogues.

Three osmophoric points have been found to be necessary for the scent of sandalwood odorants. One of these points is the bulky group in a certain distance from the osmophoric hydroxyl group. Such a hydrophobic moiety is part of the trimethylcyclopentenyl derivatives, the so called campholenals, among them many are known to exert a strong and long lasting sandalwood odor. In continuation of our SAR-studies of sandalwood odorants four isophorone analogues of beta-santalol have been synthesized. The hydrophobic region of these new isophorone derivatives is now a trimethylcyclohexene nucleus, so to speak an extension of the cyclopentene part of the campholenals by one methylene group. This modification changes the sandalwood odor drastically to woody odor notes, reminiscent only to sandalwood odor. The environs of the crowded trimethylcyclohexene nucleus demonstrate the sensitivity of sandalwood odor on the shape of the hydrophobic, bulky part of beta-santalol analogues.

Evaluation of the harmonizing effect of ylang-ylang oil on humans after inhalation.

Scientific evaluations of the effects of fragrances on humans are rather scarce. The aim of this investigation was to study the effects of ylang-ylang oil (Cananga odorata, Annonaceae) on hu-man physiological parameters and self-evaluation. Twenty-four healthy volunteers participated in the experiments. Fragrances were administered by inhalation. Physiological parameters recorded were skin temperature, pulse rate, breathing rate and blood pressure. Self-evaluation was assessed in terms of alertness, attentiveness, calmness, mood, relaxation and vigor. Additionally, fragrances were rated in terms of pleasantness, intensity and effect. The present investigation showed that ylang-ylang oil may be characterized by the concept of "harmonization" rather than relaxation/sedation. Compared to an odorless placebo, ylang-ylang oil caused significant decreases in blood pressure and pulse rate as well as significant increases of subjective attentiveness and alertness. Correlational analyses revealed that the observed effects are mainly due to a subjective odor experience.

Evaluation of the effects of East Indian sandalwood oil and alpha-santalol on humans after transdermal absorption.

The aim of the study was to investigate the effects of East Indian sandalwood oil ( Santalum album, Santalaceae) and alpha-santalol on physiological parameters as well as on mental and emotional conditions in healthy human subjects after transdermal absorption. In order to exclude any olfactory stimulation, the inhalation of the fragrances was prevented by breathing masks. Eight physiological parameters, i. e., blood oxygen saturation, blood pressure, breathing rate, eye-blink rate, pulse rate, skin conductance, skin temperature, and surface electromyogram were recorded. Subjective mental and emotional condition was assessed by means of rating scales. While alpha-santalol caused significant physiological changes which are interpreted in terms of a relaxing/sedative effect, sandalwood oil provoked physiological deactivation but behavioral activation. These findings are likely to represent an uncoupling of physiological and behavioral arousal processes by sandalwood oil.

Antimicrobial study of essential oils of Ocimum gratissimum leaves and Zanthoxylum xanthoxyloides fruits from Cameroon.

An investigation of antimicrobial activities of essential oils of fresh leaves of Ocimum gratissimum and the essential oil of the dried fruits of Zanthoxylum xanthoxyloides was carried out. The essential oils showed extensive inhibition zones and are, therefore, effective antimicrobial systems.

Synthesis and olfactoric activity of side-chain modified beta-santalol analogues.

Three osmophoric points have been postulated to be necessary for the sandalwood scent of beta-santalol derivatives. One of these points, close to the hydroxyl group, is highly specific on the stereochemistry and, in particular, on the molecular shape. The role of the 2-methyl group in the side chain of beta-santalol derivatives was studied by replacement through a hydrogen atom, an ethyl or an isopropyl group. It turns out that any change at the 2-methyl substituent leads to the complete loss of sandalwood odour.

Prediction of the aroma quality and the threshold values of some pyrazines using artificial neural networks.

An artificial neural network is used to predict both the classification of aroma compounds and their flavor impression threshold values for a series of pyrazines. The classification set consists of 98 compounds (32 green, 43 bell-pepper, and 23 nutty smelling pyrazines), and the regression sets consist of 24 green and 37 bell-pepper odorous pyrazines. The best classification of the three aroma impressions (93.7%) is obtained by using a multilayer perceptron network architecture. To predict the threshold values of bell-pepper fragrance, a standard Pearson R correlation coefficient of 0.936 for the training set, 0.912 for the verification set, and 0.926 for the test set is received with two hidden layers consisting of two and one neurons. The network for the threshold prediction of the class of green-smelling pyrazines with one hidden layer containing three neurons turns out to be the best with a standard Pearson R correlation coefficient of 0.859 for the training, 0.918 for the verification, and 0.948 for the test set. These good correlations show that artificial neural networks are versatile tools for the classification of aroma compounds.

Percutaneous absorption of the montoterperne carvone: implication of stereoselective metabolism on blood levels.

The purpose of this study was to determine whether an enantioselective difference in the metabolism of topically applied R-(-)- and S-(+)-carvone could be observed in man. In a previous investigation we found that R-(-)- and S-(+)-carvone are stereoselectively biotransformed by human liver microsomes to 4R,6S-(-)- and 45,6S-(+)-carveol, respectively, and 4R,6S-(-)-carveol is further glucuronidated. We therefore investigated the metabolism and pharmacokinetics of R-(-)- and S-(+)-carvone in four healthy subjects using chiral gas chromatography as the analytical method. Following separate topical applications at a dose of 300 mg, R-(-)- and S-(+)-carvone were rapidly absorbed, resulting in significantly higher Cmax levels for S-(+)-carvone (88.0 vs 23.9 ng mL(-1)) and longer distribution half-lives (t(1/2alpha)) (19.4 vs 7.8 min), resulting in 3.4-fold higher areas under the blood concentration-time curves (5420 vs 1611 ng min mL(-1)). The biotransformation products for both enantiomers in plasma were below detection limit. Analysis of control- and beta-glucuronidase pretreated urine samples, however, revealed a stereoselective metabolism of R-(-)-carvone to 4R,6S-(-)-carveol and 4R,6S-(-)-carveol glucuronide. No metabolites could be found in urine samples after S-(+)-carvone application. These data indicate that stereoselectivity in phase-I and phase-II metabolism has significant effects on R-(-)- and S-(+)-carvone pharmacokinetics. This might serve to explain the increased blood levels of S-(+)-carvone.

The influence of essential oils on human attention. I: alertness.

Scientific research on the effects of essential oils on human behavior lags behind the promises made by popular aromatherapy. Nearly all aspects of human behavior are closely linked to processes of attention, the basic level being that of alertness, which ranges from sleep to wakefulness. In our study we measured the influence of essential oils and components of essential oils [peppermint, jasmine, ylang-ylang, 1,8-cineole (in two different dosages) and menthol] on this core attentional function, which can be experimentally defined as speed of information processing. Substances were administered by inhalation; levels of alertness were assessed by measuring motor and reaction times in a reaction time paradigm. The performances of the six experimental groups receiving substances (n = 20 in four groups, n = 30 in two groups) were compared with those of corresponding control groups receiving water. Between-group analysis, i.e. comparisons between experimental groups and their respective control groups, mainly did not reach statistical significance. However, within-group analysis showed complex correlations between subjective evaluations of substances and objective performance, indicating that effects of essentials oils or their components on basic forms of attentional behavior are mainly psychological.

Effects of chiral fragrances on human autonomic nervous system parameters and self-evaluation.

The effects of chiral fragrances (enantiomers of limonene and carvone) on the human autonomic nervous system (ANS) and on self-evaluation were studied in 20 healthy volunteers. Each fragrance was administered to each subject by inhalation using an A-A-B design. Individuals were tested in four separate sessions; in one session one fragrance was administered. ANS parameters recorded were skin temperature, skin conductance, breathing rate, pulse rate, blood oxygen saturation and systolic as well as diastolic blood pressure. Subjective experience was assessed in terms of mood, calmness and alertness on visual analog scales. In addition, fragrances were rated in terms of pleasantness, intensity and stimulating property. Inhalation of (+)-limonene led to increased systolic blood pressure, subjective alertness and restlessness. Inhalation of (-)-limonene caused an increase in systolic blood pressure but had no effects on psychological parameters. Inhalation of (-)-carvone caused increases in pulse rate, diastolic blood pressure and subjective restlessness. After inhalation of (+)-carvone increased levels of systolic as well as diastolic blood pressure were observed. Correlational analyses revealed that changes in both ANS parameters and self-evaluation were in part related to subjective evaluation of the odor and suggest that both pharmacological and psychological mechanisms are involved in the observed effects. In conclusion, the present study indicates that: (i) prolonged inhalation of fragrances influences ANS parameters as well as mental and emotional conditions; (ii) effects of fragrances are in part based on subjective evaluation of odor; (iii) chirality of odor molecules seems to be a central factor with respect to the biological activity of fragrances.

Threshold-based structure-activity relationships of pyrazines with bell-pepper flavor.

Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (CoMFA) are applied in order to explain the aroma of 46 bell-pepper aroma compounds. Biological activities log(1/c) values are used, where c stands for the detection threshold value of the aroma compound in water. Results of conventional QSAR and CoMFA are both satisfactory in statistical significance and predictive ability. We construct a qualitative model using the graphic features of CoMFA together with the results of "classical" QSAR analysis, which is performed by multiple linear regression. Finally, the human olfactory detection threshold values of excluded pyrazines are successfully predicted. This makes CoMFA and QSAR two important tools for designing new aroma compounds and in elucidating the mechanism of odor-receptor interaction.

Stereoselective metabolism of the monoterpene carvone by rat and human liver microsomes.

The large amounts of carvone enantiomers consumed as food additives and in dental formulations justifies the evaluation of their biotransformation pathway. The in-vitro metabolism of R-(-)- and S-(+)-carvone was studied in rat and human liver microsomes using chiral gas chromatography. Stereoselective biotransformation was observed when each enantiomer was incubated separately with liver microsomes. 4R, 6S-(-)-Carveol was NADPH-dependently formed from R-(-)-carvone, whereas 4S, 6S-(+)-carveol was produced from S-(+)-carvone. Metabolite formation followed Michaelis-Menten kinetics exhibiting a significant lower apparent Km (Michaelis-Menten Constant) for 4R, 6S-(-)-carveol compared with 4S, 6S-(+)-carveol in rat and human liver microsomes (28.4+/-10.6 microM and 69.4+/-10.3 microM vs 33.6+/-8-55 microM and 98.3+/-22.4 microM). The maximal formation rate (Vmax) determined in the same microsomal preparations yielded 30.2+/-5.0 and 32.3+/-3.9 pmol (mg protein)(-1) min(-1) in rat liver and 55.3+/-5.7 and 65.2+/-4.3 pmol (mg protein)(-1) min(-1) in human liver microsomes. Phase II conjugation of the carveol isomers by rat and human liver microsomes in the presence of UDPGA (uridine S'-diphosphogluaronic acid) only revealed glucuronidation of 4R, 6S-(-)-carveol. Vmax for glucuronide formation was more than 4-fold higher in the rat liver compared with human liver preparations (185.9+/-34.5 and 42.6+/-7.1 pmol (mg protein)(-1) min(-1), respectively). Km values, however, showed no species-related difference (13.9+/-4.1 microM and 10.2+/-2.2 microM). This study demonstrated stereoselectivity in phase-I and phase-II metabolism for R-(-)- and S-(+)-carvone and might be predictive for carvone biotransformation in man.

Analysis of leaf volatiles of Zanthoxylum gillettii used in folk medicine of Cameroon.

The essential oil and the corresponding headspace sample of the leaves of ZONTHIOXYLUM GILLETTII (Rutaceae) were analyzed by gas chromatographic-spectroscopic and olfactoric methods. Mainly monoterpenes such as myrcene, TRANS-beta-ocimene, limonene, camphene, alpha- and beta-pinene which are impact compounds were found in the essential oil and headspace sample. Sesquiterpenes such as beta-caryophyllene, alpha- and beta-farnesene, beta-bisabolol, gamma-cadinene and nerolidol and alphatic components such as 2-undecanone and dodecanal were also identified and contribute to the typical odor impression as well as to the reported therapeutic properties of this ZONTHOXYLUM species.

Antimicrobial activity of Pelargonium essential oils added to a quiche filling as a model food system.

Eight essential oils obtained by steam distillation from the scented leaves of Pelargonium species and cultivars were added at 250, 500 and 1000 ppm to a quiche filling, inoculated with either Saccharomyces ludwigii or Zygosaccharomyces bailii (at 10(8) cfu g-1), Salmonella enteriditis or Listeria innocua (at 10(9) cfu g-1). The quiche fillings were then kept at 25 degrees C for 24 h and the residual number of micro-organisms determined using the pour plate technique. There was an effective antimicrobial activity by the Pelargonium essential oils at 250 ppm, comparable with that of commercial thyme oil, an excellent antimicrobial agent, against Saccharomyces ludwigii and Zygosaccharomyces bailii, and a lesser inhibition compared with commercial thyme against Salm, enteriditis. There was a greater diversity of activity against L. innocua, which was in some cases more effective than commercial thyme oil. At 500 ppm, there was a greatly increased inhibition of microbial growth using the Pelargonium essential oils, which was comparable with that of commercial thyme, clove, geranium and coriander oils. As there is no evidence for the toxicity of any of these novel Pelargonium oils, and their odour does not make the delicately flavoured quiche filling unpalatable, there is a strong potential for their use in food processing.

Comparative antibacterial effects of novel Pelargonium essential oils and solvent extracts.

The scented leaves of a number of Pelargonium (Geraniaceae) species and cultivars were extracted using steam distillation, petroleum spirit and methanol. The extracts were assessed for their antibacterial activity in vitro against Staphylococcus aureus, Proteus vulgaris, Bacillus cereus and Staph. epidermidis. The results indicated substantial antibacterial activity and suggested that Pelargonium essential oils could be used as novel antibacterial agents. The methanolic and petroleum spirit extracts were more potent antibacterial agents than the steam-distilled volatile samples. The results suggest that Pelargonium essential oils and solvent extracts could be used as novel food or cosmetic antimicrobial agents.

Structure-activity relationships of sandalwood odorants: synthesis and odour of methyl-beta-santalol.

The synthesis and odour properties of the new santalol analogue, methyl-beta-santalol, are described. The additional methyl group adjacent to the hydroxyl function of the standard molecule, beta-santalol, deprives the new compound of the sandalwood note. The synthesis and the odour evaluation of this compound supports the proposed model for sandalwood fragrance as it shows that the methyl group located at the osmophoric center prevents association of the molecule with the hypothetical receptor.

Pharmacokinetic studies of the fragrance compound 1,8-cineol in humans during inhalation.

The present study was undertaken to investigate the pharmacokinetics of 1,8-cineol in human subjects during prolonged inhalation. The results showed that 1,8-cineol is well absorbed from breathing air, with a peak plasma concentration after approximately 18 min. The elimination of this fragrance compound from the blood is biphasic, with a mean distribution half-life of 6.7 min and an elimination half-life of 104.6 min.

Investigation of cytotoxic effects of 8 norbornane derivatives on 4 human cancer cell lines using the MTT assay.

A group of 8 structurally modified norbornane analogs, selected on basis of water solubility, was tested for its potential cytotoxic effects using a modified MTT assay. Four tumor cell lines, three hematological and a hepatocellular one were used as an experimental model system. Some analogs exhibited an antitumor effect which was shown to be tissue specific. The cytotoxic effect is most likely due to the nature of the side chains rather than to the basic bicyclic norbornane structure of the molecule. These results not only provide a basis for the synthesis of derivatives with effective antitumor activity, but also give some indication of the the molecular target of these compounds.

Functional imaging of effects of fragrances on the human brain after prolonged inhalation.

Beside olfactory or trigeminal stimulation of chemosensory receptor-cells some results in published literature suggest that fragrances show a direct affect on the brain. The effect of the fragrance 1,8-cineol, which was described in literature as 'stimulating', on regional and global cerebral blood flow (rCBF and gCBF) in the human brain after prolonged inhalation was investigated. The results show an increase of global-CBF without preference to primary or secondary olfactory centres after an inhalation-time of 20 min.