Angela Bassoli

Taste-guided identification of high potency TRPA1 agonists from Perilla frutescens

Perilla frutescens is a food plant widely used in Asian cuisine. This plant was investigated for its interesting taste and somatosensory properties. Perillaldehyde and perillaketone are among the components of the aromatic extracts from P. Frutescens. These compounds were shown here to activate the cloned TRPA1 channel when expressed in an heterologous cell system and are therefore suggested to be responsible for the chemesthetic properties of this plant.

Acyclic and cyclic urea formation via the cobalt-catalysed oxidative carbonylation of aromatic primary amines

Abstract The N,N-bis(salicylidene)ethylenediaminocobalt(II)-catalysed oxidative carbonylation of aromatic primary amines in methanol gives ureas in good yields, with small amounts of carbamates and azo derivatives. Ortho-substituted aromatic amines also give cyclic ureas via a metal-induced oxidative carbonylation-cyclisation pathway.

Synthesis of carbazole by Ru3(CO)12-catalyzed reductive carbonylation of 2-nitrobiphenyl: the crystal and molecular structure of Ru3(μ3-NC6H4-o-C6H5)2(CO)9

Abstract The Ru 3 (CO) 12 -catalyzed reductive carbonylation of 2-nitrobiphenyl 1 in acetonitrile gives carbazole 2 and 2-aminobiphenyl 3 . Compound 3 is the major reaction product in tetrahydrofuran, toluene, toluene-methanol, thiophene and cis -cyclooctene. Some products deriving from intermolecular insertion into the solvent are also found with acetonitrile, thiophene and cis -cyclooctene. By reaction of 2-nitrosobiphenyl 7 with Ru 3 (CO) 12 , the nitrene complex Ru 3 (μ 3 -NC 6 H 4 - o -C 6 H 5 ) 2 (CO) 9 11 has been isolated and its crystal structure has been determined. Compound 11 is orthorhombic, space group P2 1 2 1 2 1 with a = 11.160(4), b = 11.472(2), c = 25.478(6) A, Z = 4, R = 0.019, R w = 0.028, for 3161 independent reflections with I >3σ( I ). The ortho -substituent phenyl ring of the nitrene ligands in compound 11 is free to rotate around the CC bond and thus can assume the proper arrangement to allow insertion of nitrogen into the aromatic CH bond to give carbazole 2 . This possibility has been confirmed by treating 11 with CO (50 bar) at 220°C to obtain 2 and Ru 3 (CO) 12 .

The taste of D- and L-amino acids: In vitro binding assays with cloned human bitter (TAS2Rs) and sweet (TAS1R2/TAS1R3) receptors

The taste of different enantiomeric forms of amino acids has been deeply investigated because it represents the most impressive case of correlation between stereochemistry and flavour. Herein, we aimed to elucidate the molecular activity of d- and l-amino acids using an in vitro system based on a cellular model overexpressing sweet and bitter receptors, and to analyse the correlation between in vitro and sensory studies. With our work we demonstrated specific enantiomeric activities for several amino acids on TAS1R2-TAS1R3 sweet receptor. Moreover, we proved interaction of tryptophan and phenylalanine with a specific group of TAS2Rs bitter receptors, confirming and improving the results recently obtained in the tasting of amino acids. In addition, we provide the first systematic analysis of l- and d-amino acid actions on the sweet heterodimeric receptor.

Metal carbonyl catalyzed reductive carbonylation of substituted nttrobenzenes in presence of alkenes as solvents

Abstract Several nitrobenzene derivatives were submitted to reaction with carbon monoxide in alkene solvents in the presence of catalytic amounts of Ru3(CO)12. Ureas and amines were formed in this reaction, and the secondary amine derived from insertion of the nitrene intermediate at the allylic position of the alkene solvent was a secondary product. The influence of the electronic factor of the substituents on the urea vs. amine ratio is discussed.

Quantitative Structure‐Activity Relationships of Sweet Isovanillyl Derivatives

Isovanillyl derivatives constitute a large class of sweet compounds in which there is a high degree of structural similarity and a wide range of biological activity, the relative sweetness RS spanning from 50 to 10 000 times with respect to sucrose. This paper describes the results obtained by applying statistical models to develop QSARs for these derivatives. For a set of 14 compounds (set 1) appropriate physicochemical parameters for regression equations were selected using the genetic algorithm method. The best equation indicates a very close correlation (N=14, ND=5, r2=0.982, Rcv2=0.942, LOF=0.074, PRESS=0.271, SPRESS=0.184, SDEP=0.139). Good results have also been obtained by Molecular Field Analysis (MFA) applied to the same set of compounds (N=14, ND=4, r2=0.957, rcv2=0.925, LOF=0.044, PRESS=0.348, SPRESS=0.196, SDEP=0.158). QSARs have also been derived for a larger set of 41 compounds (set 2, including set 1, plus other 27 compounds) with a much larger variety of structural types. These compounds have been divided into a training set of 35 compounds and a test set of 6 compounds. The most significant QSAR obtained using physicochemical parameters (N=35, ND=6, r2=0.673, rcv2=0.522, LOF 0.337, PRESS=7.432, SPRESS=0.515, SDEP=0.461) proved less successful than one using MFA parameters (N=35, ND=6, r2=0.746, rcv2=0.607, LOF 0.261, PRESS=6.110, SPRESS=0.467, SDEP=0.418). PRESS values for the test set were 4.079 and 1.962 respectively showing that the MFA data had more predictive power. Equations with different numbers of descriptors were compared and it was concluded that the LOF which is dependent upon the number of parameters used as well as the sum of squares is a suitable measure of equation quality. These equations were also validated by scrambling the experimental data which gave significantly worse agreement than the real data except when an excessive number of descriptors was used.

Triruthenium dodecacarbonyl-catalyzed reductive carbonylation of nitroarenes : cyclization, carbon monoxide insertion and reduction. An overview

Abstract Several ortho-nitrobiarenes and dinitrobiarenes were submitted to Ru3(CO)12-catalyzed reductive carbonylation in acetonitrile and in cis-cyclooctene. The main reaction products were the corresponding amines and five-membered heterocycles such as indoles and imidazoles. Small amounts of six-membered cyclization products such as acridane dimers, phenothiazine, quinoxalines were also found. The cyclization to indole occurred also at room temperature under irradiation or with zinc. The use of cis-cyclooctene as the solvent also trapped the nitroso intermediates. Nitrones were formed in this reaction and were suggested to be intermediate in certain cyclizations. Force-field calculations allowed to suggest organoruthenium intermediates in these reactions.

Isovanillyl sweeteners. From molecules to receptors

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.

Analogues of perillaketone as highly potent agonists of TRPA1 channel.

Transient receptor potential (TRP) channels represent interesting molecular target structures involved in a number of different physiological and pathophysiological systems. In particular, TRPA1 channel is involved in nociception and in sensory perception of many pungent chemesthetic compounds, which are widespread in spices and food plants, including Perilla frutescens. A natural compound from P. frutescens (isoegomaketone) and 16 synthetic derivatives of perillaketone have been prepared and tested in vitro on rTRPA1 expressed in HEK293 cells and their potency, efficacy and desensibilisation activity measured. Most derivatives proved to be high potency agonists of TRPA1, with a potency higher than most natural agonists reported in the literature. These furylketones derivatives, represent a new class of chemical structures active on TRPA1 with many potential applications in the agrifood and pharmaceutical industry.

Taste-Active Compounds in a Traditional Italian Food: ‘Lampascioni’

Nature is a rich source of taste‐active compounds, in particular of plant origin, many of which have unusual tastes. Many of these are found in traditional food, where spontaneous plants are used as ingredients. Some taste‐active compounds were identified in the bulbs of Muscari comosum, a spontaneous plant belonging to the family of the Liliaceae, very common in the Mediterranean area, and used in traditional gastronomy (called ‘lampascioni’ in South Italy). The bulbs were extracted with a series of solvents of different polarity. The different fractions were submitted to a preliminary sensory evaluation, and the most interesting ones, characterized by a strong bitter taste and some chemestetic properties, were submitted to further purification and structural analysis. From the ethereal extract, several 3‐benzyl‐4‐chromanones and one stilbene derivative were isolated. Pure compounds were examined for their taste activity by means of sensory evaluation, and proved to be responsible for the characteristic taste of this food. Some of these compounds have been synthesized de novo to confirm their structure.