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Abstract: The natural compound phyllodulcin and its derivatives, the so-called isovanillic sweeteners, are a large and homogeneous group of sweet compounds. This paper describes the results on the systematic analysis of the taste profile of some representative compounds of this family. They show a marked sweet taste but also some afternotes as a licorice/anise flavor and a cooling effect that have been studied by means of time-intensity techniques. A comparison of data on sweet taste intensity assessed by sensory evaluation and by affinity tests with cloned human sweet taste receptor hT1R2/hT1R3 shows that for this homogeneous class of compounds—in vivo and in vitro estimates of sweet taste intensity are consistent.

Food compounds with a bitter taste have a role in human health, both for their capability to influence food choice and preferences and for their possible systemic effect due to the modulation of extra-oral bitter taste receptors (TAS2Rs). Investigating the interaction of bitter food compounds with TAS2Rs is a key step to unravel their complex effects on health and to pave the way to rationally design new additives for food formulation or drugs. Here, we propose a collection of food bitter compounds, for which in vitro activity data against TAS2Rs are available. The patterns of TAS2R subtype-specific agonists were analyzed using scaffold decomposition and chemical space analysis, providing a detailed characterization of the associations between food bitter tastants and TAS2Rs.

Sweet, umami and bitter tastes are in large part mediated by G-protein coupled receptors of taste type 1 (TAS1R) and taste type 2 (TAS2R) families. The genetics and molecular function of TAS receptors has been extensively explored, but more recently studies have identified these receptors in extra-oral locations. This has opened new perspectives on the function and evolutionary role of these receptors, and given rise to the possibility of using them as targets for personalized health interventions. In addition, these findings have generated new questions about the genetics of TAS1Rs and TAS2Rs that await answers. Here, we address the questions that we consider to be the most salient and intriguing and suggest more comprehensive theoretical and experimental approaches that could help to solve them.

In this paper, the chemical composition of Telfairia pedataseeds and oil is discussed. This crop belongs to the family of Cucurbitaceae. Unroasted seeds and oil obtained from roasted seeds were collected during a study trip in Tanzania. Oil from unroasted seeds was extracted in the lab using hexane. The seeds contain approximately 60 (% m/m) of oil and 30 (% m/m) of protein, being the remaining amount represented by crude fiber, carbohydrates and mineral constituents. The protein fraction contains glutamic acid, arginine, aspartic acid and leucine as the most representative amino acids. The fatty acid composition is a common one, being palmitic, linoleic, stearic and oleic acids, the most important fatty acids detected. No difference was found in fatty acid composition between oils extracted from roasted and unroasted seeds. On the contrary, the oil obtained from roasted seeds shows a higher concentration in sterols and tocopherols while the distribution between the different constituents remains the same.

The extent to which variation in taste perception influences food preferences is, to date, controversial. Bitterness in food triggers an innate aversion that is responsible for dietary restriction in children. We investigated the association among genetic variations in bitter receptor TAS2R38 and food choices in healthy children in the Mediterranean area, to develop appropriate tools to evaluate the relation among genetic predisposition, dietary habits, and feeding disorders. The aims of the study were to get a first baseline picture of taste sensitivity in healthy adults and their children and to explore taste sensitivity in a preliminary sample of obese children and in samples affected by functional gastrointestinal diseases.

The extent to which variation in taste perception influences food preferences is, to date, controversial. Bitterness in food triggers an innate aversion that is responsible for dietary restriction in children. We investigated the association among genetic variations in bitter receptor TAS2R38 and food choices in healthy children in the Mediterranean area, to develop appropriate tools to evaluate the relation among genetic predisposition, dietary habits, and feeding disorders. The aims of the study were to get a first baseline picture of taste sensitivity in healthy adults and their children and to explore taste sensitivity in a preliminary sample of obese children and in samples affected by functional gastrointestinal diseases. Individuals (98 children, 87 parents, 120 adults) were recruited from the general population in southern Italy. Bitterness sensitivity was assessed by means of a suprathreshold method with 6-propyl-2-thiouracil. Genomic DNA from saliva was used to genotype individuals for 3 polymorphisms of TAS2R38 receptor, A49P, A262 V, and V296I. Food intake was assessed by a food frequency questionnaire. Children's taste sensation differed from that of adults: we observed a higher frequency of supertasters among children even in the mother–child dyads with the same diplotypes. Among adults, supertaster status was related with proline-alanine-valine (taster allele) homozygous haplotype, whereas supertaster children were mainly heterozygous. Regarding the food choices, we found that a higher percentage of taster children avoided bitter vegetables or greens altogether compared with taster adults. Taster status was also associated with body mass index in boys. Greater sensitivity to 6-propyl-2-thiouracil predicts lower preferences for vegetables in children, showing an appreciable effect of the genetic predisposition on food choices. None of the obese boys was a supertaster.

The physiology of human taste experienced an unprecedented expansion of knowledge brought forward by modern genetics and molecular biology. In the last 10 years, the cellular organization of taste receptors from taste buds distributed in the various papillae of the tongue and the soft palate was enlightened. This molecular revolution rapidly expanded over and above the tongue because several papers reporting the presence of taste receptors in nongustatory tissues (eg, gut, brain) appeared. Hence, the issue of perception of food molecules is no longer confined to the field of nutrition and food preferences, but is rapidly expanding to gastrointestinal (GI) function and, possibly, to gut dysfunction. In children, functional GI diseases are strictly correlated to food preference and food aversion and up to now, the tools to address these kinds of problems were basic nutritional requirements, familial good sense, and a lot of patience: blunt tools to face extremely common and disturbing complaints. The fact that taste receptors are expressed down the whole of the intestinal tract is of particular interest because of their possible role in digestive behavior and absorption of nutrients; therefore, recent and future discoveries in this field will make possible the fine-tuning of new, sharper tools to treat children with functional GI diseases.

The physiology of human taste experienced an unprecedented expansion of knowledge brought forward by modern genetics and molecular biology. In the last 10 years, the cellular organization of taste receptors from taste buds distributed in the various papillae of the tongue and the soft palate was enlightened. This molecular revolution rapidly expanded over and above the tongue because several papers reporting the presence of taste receptors in nongustatory tissues (eg, gut, brain) appeared. Hence, the issue of perception of food molecules is no longer confined to the field of nutrition and food preferences, but is rapidly expanding to gastrointestinal (GI) function and, possibly, to gut dysfunction. In children, functional GI diseases are strictly correlated to food preference and food aversion and up to now, the tools to address these kinds of problems were basic nutritional requirements, familial good sense, and a lot of patience: blunt tools to face extremely common and disturbing complaints. The fact that taste receptors are expressed down the whole of the intestinal tract is of particular interest because of their possible role in digestive behavior and absorption of nutrients; therefore, recent and future discoveries in this field will make possible the fine-tuning of new, sharper tools to treat children with functional GI diseases.

Abstract: The natural compound phyllodulcin and its derivatives, the so-called isovanillic sweeteners, are a large and homogeneous group of sweet compounds. This paper describes the results on the systematic analysis of the taste profile of some representative compounds of this family. They show a marked sweet taste but also some afternotes as a licorice/anise flavor and a cooling effect that have been studied by means of time-intensity techniques. A comparison of data on sweet taste intensity assessed by sensory evaluation and by affinity tests with cloned human sweet taste receptor hT1R2/hT1R3 shows that for this homogeneous class of compounds—in vivo and in vitro estimates of sweet taste intensity are consistent.

A number of derivatives of camptothecin with a polyamine chain linked to position 7 of camptothecin via an amino, imino, or oxyiminomethyl group were synthesized and tested for their biological activity. All compounds showed marked growth inhibitory activity against the H460 human lung carcinoma cell line. In particular, the iminomethyl derivatives where the amino groups of the chain were protected with Boc groups exhibited a high potency, with IC50values of ∼10-8M. The pattern of DNA cleavage in vitro and the persistence of the cleavable ternary complex drug−DNA−topoisomerase I observed with polyamine conjugates containing free amino groups support a contribution of specific drug interaction with DNA as a determinant of activity. Modeling of compound 7cin the complex with topoisomerase 1 and DNA is consistent with this hypothesis. The lack of a specific correlation between stabilization of the cleavable complex and growth inhibition likely reflects multiple factors including the cellular pharmacokinetic behavior related to the variable lipophilicity of the conjugate, and the nature and linkage of the polyamine moiety.

A new class of synthetic compounds with chemesthetic activity has been identified. They have been designed ex-novo by structural similarity with known cooling compounds such as menthol, icilin and cyclic ketoenamines. 19 new derivatives have been obtained easily and in high yields by Goldberg arylation or lactam ring closure on the appropriate phenol or benzoic acid derivative. The synthetic procedures are suitable for gram-scale preparation, and the products are stable and easy to purify. 17 new compounds were submitted to preliminary sensory evaluation, and 3 of them showed cooling activity and, in some cases, tingling sensation in the oral cavity. These N-aryl lactams seem to be an interesting class of compounds to be enlarged in order to derive structure-activity relationships. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The sweet natural compound monatin 1 has two stereogenic centers, and the 2S,4S absolute configuration has been attributed previously to the natural isomer. Among the four stereoisomers of monatin, three of them, particularly the 2R,4R isomer, tastes intensely sweet. The conformations of the four compounds have been studied by means of molecular modelling techniques. Both the diastereoisomeric forms show strong intramolecular hydrogen bonds which involve different functional groups and give rise to two different minimum energy conformations. The tertiary alcohol group in monatin seems to be indirectly involved in the generation of the taste, acting as an important contraint in generating the active conformation. The most important glucophores have been identified in the terminal –NH3+ and –COO– groups and in the indole ring by comparison with known topological models of sweet compounds and through the synthesis of appropriate derivatives in which some of these groups are lacking or modified. The relative affinity of each stereoisomer for its putative sweet taste receptor has been estimated semiquantitatively with the pseudoreceptor modelling technique. The predicted activity calculated with this technique is in good agreement with the experimental data and explains why the 2R,4R isomer (and not the natural 2S,4S isomer) is the sweetest of the series. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The sweet natural compound monatin 1 has two stereogenic centres and the (2S,4S) absolute configuration has been attributed to the natural isomer. We obtained all four stereoisomers as pure compounds by a six-step synthetic sequence. The stereogenic centre at C-4 was introduced stereoselectively by a regio- and enantiospecific enzymatic hydrolysis of the racemic ethyl dicarboxylate 4 using a protease from Aspergillus oryzae. The absolute configuration of the intermediate products was assigned by X-ray diffraction of chiral derivatives. The stereogenic centre at C-2 was introduced non-specifically, and the resulting diastereomeric mixtures were separated by RP-HPLC. The absolute configurations of the final products were established by comparing retention times on a chiral HPLC column with those of known samples. The four stereoisomers were submitted to tasting trials and three of them, particularly the (2R,4R) isomer, were found to be intensely sweet. A sample of natural monatin analysed under the same conditions is shown to contain all the four stereoisomers. The relative stereoisomeric content in the plant, as well as the possible isomerisation of the chiral centres during extraction and manipulation of monatin samples, are important points that need to be clarified by extensive analysis of the natural extracts. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Systematic modification of the structure of the sweet natural compound phyllodulcin, containing the isovanillyl glucophoric group, led to the synthesis of about 120 compounds. Features of the heterocyclic ring conferring high sweetness potency were identified. A strong increase in sweetness was obtained by the introduction of sulfur atoms in the ring and by separation of the enantiomers. Results of the quantitative structure­activity relationship (QSAR) studies on this series are reported. Application of the pseudoreceptor modeling approach afforded a three-dimensional binding site model for isovanillyl sweeteners. Extension of this methodology to a large group of structurally diverse compounds, including the commonly used sweeteners, gave a general pseudoreceptor for the sweet compounds, consisting of 16 amino acids. This pseudoreceptor, which has the peculiarity of giving a semiquantitative evaluation of the sweetness intensity, could be used as a valid tool to model the ligand­receptor interactions and to suggest some clues about the identification of a possible binding site once the receptor protein(s) are obtained.

Using pseudoreceptor modelling, we have derived a three-dimensional binding-site model for the structurally uncharacterised sweet-taste receptor. The receptor model was derived based on 17 sweet compounds of the isovanillyl class (4-methoxy-3-hydroxybenzyl) as the training set and consists of nine key amino-acid residues embedded in a hydrophobic receptor cavity. The underlying technology (software PrGen) allows for a dynamical treatment of the ligand–receptor complex (ligand equilibration and Monte-Carlo scanning of receptor space) as well as for receptor-mediated ligand alignment. Free energies of ligand binding are estimated based on ligand–receptor interactions, ligand desolvation energy, change of ligand internal energy and change of ligand entropy upon receptor binding.The validity of the receptor model has been assessed by using a test set of eight isovanillyl sweet compounds different from the training set. For these ligands, the obtained binding-site surrogate is capable of predicting free energies of ligand binding, ΔG °, to within 0.99 kcal mol–1 (rms) of their experimental value, corresponding to an uncertainty in the sweetness of a factor of 5.5. Maximal individual errors of predicted sweetnesses do not exceed a factor of 18.

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