The prevalence of chronic kidney disease (CKD) is increasing and frequently progresses to end-stage renal disease. There is an urgent demand to discover novel markers of disease that allow monitoring disease progression and, eventually, response to treatment. To identify such markers, and as a proof of principle, we determined if a metabolite signature corresponding to CKD can be found in urine. In the discovery stage, we analyzed the urine metabolome by NMR of 15 patients with CKD and compared that with the metabolome of 15 healthy individuals and found a classification pattern clearly indicative of CKD. A validation cohort of urine samples from an additional 16 patients with CKD and 15 controls was then analyzed by (Selected Reaction Monitoring) liquid chromatography-triple quadrupole mass spectrometry and indicated that a group of seven urinary metabolites differed between CKD and non-CKD urine samples. This profile consisted of 5-oxoproline, glutamate, guanidoacetate, α-phenylacetylglutamine, taurine, citrate, and trimethylamine N-oxide. Thus, we identified a panel of urine metabolites differentially present in urine that may help identify and monitor patients with CKD.
Novel [60]fullerene-steroid hybrids have been synthesized by Bingel-Hirsch cyclopropanation reaction between C 60 and steroid malonates, leading to conjugates in which a [60]fullerene unit is connected to one or two dehydroepiandrosterone moieties, an important naturally occurring steroid hormone. The obtained derivatives have been fully characterized by a whole set of instrumental techniques in order to determine their chemical structure. Moreover, their electrochemical properties, investigated by cyclic voltammetry, revealed the presence of three reversible reduction waves for both hybrids. Furthermore, Transmission Electron Microscopy studies allowed to [a
Multidimensional nuclear magnetic resonance plays a number of essential roles in present day spectroscopy. It is also an integral part of the image formation protocol in magnetic resonance imaging (MRI).[1] Traditional two-dimensional experiments are intrinsically time consuming, because many t 1 increments have to be acquired to obtain twodimensional spectra with adequate digital resolution in the indirect dimension.[2] Proposals for accelerating multidimensional NMR spectroscopy include non-Fourier transform schemes, [3] the acquisition of multiple NMR spectra in a single experiment, [4] and "single scan" multidimensional NMR spectroscopy, also called ultrafast NMR spectroscopy (UF NMR), have been introduced. The latter methodology was inspired by echo planar imaging (EPI) [5] and was developed by Frydman et al. [6] It permits the collection of complete multidimensional NMR data sets within a single continuous acquisition. This new methodology is compatible with existing standard (TOCSY, HSQC, MRI) and recently described combined multidimensional pulse sequences, [7] and it can be implemented with conventional hardware. This attractive feature enables ultrafast NMR to examine dynamic processes, that is, organic reactions and their mechanisms as they happen in real time.[8] Figure 1 shows the schematic of the two-dimensional UF-TOCSY sequence used.[9] The sequence uses a continuous spatial encoding [10] which was implemented by pairs of RF pulses which excite/store spins over the full length, L, of the sample. The sample was swept over intervals t 1 max /2 whereas AE G e external gradients were applied. The offsets of such pulses were thus chirped over a AE gG e L/2 span, and their amplitudes calibrated as effective p/2 nutations by setting gB 1 as a function of 0.25 [(2 gG e L/t 1 max )] 1/2 .We focused our attention on one-pot syntheses of pyrimidines and similar heterocyclic compounds, which we had previously developed. [11] Pyrimidines are an important class of compounds which includes numerous natural, pharmaceutical, and functional materials.[12] Elegant new procedures have been described [13] and revealed decisive information on the mechanistic details of the reaction between carbonyl compounds and strong electrophiles such as trifluoromethanesulfonic acid anhydride (Tf 2 O). [11,14] In spite of the importance of these reactions, no spectroscopic confirmation of the postulated intermediates or kinetic data on the reaction have been reported.Using a medium field 500 MHz spectrometer, we have now applied UF NMR methodology to monitor the reaction between aliphatic ketones and Tf 2 O in the presence of nitriles. We have determined how the signals of the starting and final products evolve as they happen, in real time and attempted to detect the presence of intermediates. We chose a symmetric aliphatic ketone, 3-pentanone (1), as the model compound to react with a two-fold amount of Tf 2 O in [D 3 ]acetonitrile, which served as both a co-reactant and solvent.Scheme 1 shows the previously proposed reaction mec...
New hybrid fullerene–steroid derivatives were prepared by using the Bingel–Hirsch protocol, by treatment of [60]fullerene with malonates bearing the appropriate steroid moieties obtained, in turn, from the functionalization of epiandrosterone, an important naturally occurring steroid hormone. Monocycloadduct C60‐steroid conjugates were obtained by functionalization of ring A or ring D of the steroid moiety. We have also described the multistep preparation of a [60]fullerene hybrid dumbbell endowed with two fullerene units connected through an epiandrosterone molecule by a cyclopropanation reaction. The new compounds have been spectroscopically characterized and their redox potentials, determined by cyclic voltammetry, reveal three reversible reduction waves for monocycloadducts (8, 9 and 11, 12), whereas dumbbell‐type derivative 10 exhibits the best electron‐accepting abilities of the Bingel‐type fullerene–steroid series. Theoretical calculations at semiempirical (AM1) and single point B3LYP‐D3/6‐31G+(d,p) levels have predicted the most stable conformations for the hybrid compounds and allow explaining the observed regioselectivity in the cyclopropanation reaction with dimalonate 7 during the synthesis of the dumbbell derivative.
The design and synthesis of fullerene-steroid hybrids by using Prato's protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five member ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, and 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene by the Re face. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C 60 .
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