A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16–18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as “metabolic disruptors”, in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.

A modified cyclodextrin containing a dansyldiethylenetriamine metal-binding group (6-deoxy-6-N-(N‘‘-dansyldiethylenetriamino)-β-cyclodextrin, CD-dien-DNS) was synthesized. The conformation of CD-dien-DNS was studied by 2D NMR (ROESY spectra) in D2O, by circular dichroism, and by fluorescence. The results were compared with those previously obtained with the analogous 6-deoxy-6-N-(N‘-dansylethylenediamino)-β-cyclodextrin (CD-en-DNS) and were consistent with the self-inclusion of the dansyl group within the macrocycle cavity. However, the orientation of the dansyl group for CD-dien-DNS was found to be equatorial, whereas for CD-en-DNS it was axial, suggesting a dependence of the orientation of the dansyl group upon the length of the linker. In the presence of lipophilic organic molecules, CD-dien-DNS showed sensing properties similar to those observed for CD-en-DNS, suggesting a similar “in-out” movement of the dansyl group, due to competitive inclusion of the guest. Unlike CD-en-DNS, CD-dien-DNS was found to be a fluorescent chemosensor for copper(II) ion, with a linear response up to a 1:1 molar ratio, suggesting that a more flexible conformation of the linker and the presence of additional binding sites allow binding of the metal ion by the amino and sulfonamidate groups. Good selectivity for Cu(II), when compared with Fe(II), Co(II), Ni(II), and Zn(II), was observed. The CD-dien-DNS copper(II) complex was shown to behave as a chemosensor for bifunctional molecules, such as amino acids. In fact, upon addition of alanine, tryptophan, and thyroxine, the negligible fluorescence intensity of Cu(CD-dien-DNS) complex was “switched on”, with a response dependent on the amino acid side chain.

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A monofunctionalized p-cyclodextrin containing a dansyl moiety, 6-cyclodextrin (CD-en-DNS, 2), was synthesized and its crystal structure determined. It was shown that the dansyl group is fully encapsulated within the cyclodextrin cavity, with the dimethylamino and sulfonyl groups emerging from opposite sides. The shape of the cavity is considerably flattened, since O(4)-0(4) distances parallel to the naphthalene ring were found to be longer than the others. The conformation of the diaminoethane linker was found to be determined by the inclusion of the dansyl group and by a hydrogen bond between the sulfonamide NH and one of the O(6)-H groups on the cyclodextrin rim. The self-inclusion features of the aromatic moiety were found to be consistent with the solution data: 'H NMR ROESY spectra suggested that the orientation of the dansyl moiety observed in the solid state was retained in aqueous solution; the circular dichroism spectrum was consistent with an axial complexation model. Fluorescence spectra showed that the inclusion of the dansyl group in the cyclodextrin cavity considerably increases the quantum yield; time-resolved fluorescence experiments showed the presence of a long-lifetime component (16.1 ns), which was attributed to the included fluorophore. The ability of 2 to act as a fluorescence sensor was evaluated by the addition of several guests of different shape: fluorescence intensity was lowered, especially upon addition of adamantanecarboxylic acid. All the data obtained were consistent with the model of the inout movement of the dansyl group from the self-included conformation observed in the solid state to a position more exposed to the bulk solvent. Copper(I1) was shown to enhance the difference in the fluorescence of 2 in the presence of guests by additional static quenching.

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