Theoretical study of the reaction mechanisms involved in the thermal intramolecular reactions of 1,6-fullerenynes

Substitution of a H atom by an alkyl group on the terminal carbon of the alkyne moiety of 1,6-fullerenynes has a strong impact on the products of the reaction undergone by this species after thermal treatment. While the reaction of 1,6-fullerenynes bearing an unsubstituted alkyne moiety results in the cycloaddition of the alkyne group to the fullerene double bond leading to cyclobutene-fused derivatives, the presence of an alkyl substituent leads to the formation of allenes. In the present work, we have performed an exhaustive theoretical analysis of all possible reaction mechanisms leading to cyclobutene-fused derivatives and allenes to offer an explanation of the reactivity differences observed. The results obtained show that formation of cyclobutene-fused derivatives occurs through a stepwise diradical reaction mechanism, while allene formation proceeds through a concerted way involving an uncommon intramolecular ene process. For the 1,6-fullerenynes bearing a substituted alkyne, the ene reaction path leading to allenes has an energy barrier somewhat lower than the stepwise diradical mechanism for the cyclobutene-fused derivative formation, thus explaining the outcome of the reaction.     

Temperature dependence of the kinetic isotope effects in thymidylate synthase. A theoretical study

In recent years, the temperature dependence of primary kinetic isotope effects (KIE) has been used as indicator for the physical nature of enzyme-catalyzed H-transfer reactions. An interactive study where experimental data and calculations examine the same chemical transformation is a critical means to interpret more properly temperature dependence of KIEs. Here, the rate-limiting step of the thymidylate synthase-catalyzed reaction has been studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) simulations in the theoretical framework of the ensemble-averaged variational transition-state theory with multidimensional tunneling (EA-VTST/MT) combined with Grote-Hynes theory. The KIEs were calculated across the same temperature range examined experimentally, revealing a temperature independent behavior, in agreement with experimental findings. The calculations show that the H-transfer proceeds with ～91% by tunneling in the case of protium and ～80% when the transferred protium is replaced by tritium. Dynamic recrossing coefficients are almost invariant with temperature and in all cases far from unity, showing significant coupling between protein motions and the reaction coordinate. In particular, the relative movement of a conserved arginine (Arg166 in Escherichia coli ) promotes the departure of a conserved cysteine (Cys146 in E. coli ) from the dUMP by polarizing the thioether bond thus facilitating this bond breaking that takes place concomitantly with the hydride transfer. These promoting vibrations of the enzyme, which represent some of the dimensions of the real reaction coordinate, would limit the search through configurational space to efficiently find those decreasing both barrier height and width, thereby enhancing the probability of H-transfer by either tunneling (through barrier) or classical (over-the-barrier) mechanisms. In other words, the thermal fluctuations that are coupled to the reaction coordinate, together with transition-state geometries and tunneling, are the same in different bath temperatures (within the limited experimental range examined). All these terms contribute to the observed temperature independent KIEs in thymidylate synthase.     

A multi-scale approach to spin crossover in Fe(II) compounds

We report here for the first time a multi-scale study on the concept of spin-crossover compounds, which integrates improved density functionals, a polarizable force field and hybrid QM/MM calculations. This multi-scale setup is applied to the temperature dependence of spin states of a Fe(II) compound with trispyrazolylborate ligands that exhibits spin-crossover. Our study shows a transition temperature of around 290 K, which is in perfect agreement with experimental results. Moreover, based on our data we provide the origin of why spin transition occurs in this iron-compound: it results directly from spin-state changes in the iron-compound that lead to more favourable electrostatic interactions for the high-spin state.     

Iododesilylation of TIPS-, TBDPS-, and TBS-substituted alkenes in connection with the synthesis of amphidinolides B/D

The C-Si bonds of triisopropylsilyl-substituted alkenes, 1,3-dienes, and related multifunctional substrates, as well as analogous C-TBDPS and C-TBS bonds, are readily and chemoselectively cleaved with NIS (or other sources of I(+), such as N-iodosaccharin, 1,3-diodohydantoin, and Ipy(2)BF(4)). The desired iodoalkenes are obtained stereospecifically without byproducts, provided that the reactions are carried out in CF(3)CHOHCF(3) and, in general, with 30 mol % of Ag(2)CO(3) (or AgOAc/2,6-lutidine) as an additive. Fragment C10-C18 of cytotoxic amphidinolides B1-B3 and D has been synthesized using this improved procedure.     

Comparison of 24-h volume and creatinine-corrected total urinary polyphenol as a biomarker of total dietary polyphenols in the Invecchiare InCHIANTI study

Polyphenols have beneficial effects on several chronic diseases but assessing polyphenols intake from self-reported dietary questionnaires tends to be inaccurate and not very reliable. A promising alternative is to use urinary excretion of polyphenols as a proxy measure of intake. The best method to assess urinary excretion is to collect 24-h urine. However, since collecting 24-h urine method is expensive, time consuming and may be difficult to implement in large population-based studies, measures obtained from spot urine normalized by creatinine are commonly used. The purpose of the study was to evaluate the correlation between polyphenols dietary intake and total urinary polyphenol excretion (TPE), expressed by both 24-h volume and urinary creatinine normalization in 928 participants from the InCHIANTI study. Dietary intake data were collected using a validated food frequency questionnaire. Urinary TPE was analyzed by Folin-Ciocalteau assay. Both urinary TPE expression models were statistically correlated (r=0.580), and the partial correlation coefficient improved (pr=0.722) after adjusting for the variables that modify the urinary creatinine excretion (i.e. gender, age, BMI, physical activity and renal function). In crude models, polyphenol intake was associated with TPE corrected by 24-h volume (r=0.211; P<0.001), but not with creatinine normalization (r=0.014; P=0.692). However, urinary TPE expressed by creatinine correction was significantly correlated with dietary polyphenols after adjusting for covariates (pr=0.113; P=0.002). We conclude that urinary TPE expressed by 24-h volume is a better biomarker of polyphenol dietary intake than by urinary creatinine normalization. After covariate adjustment, both can be used for studying the relationships between polyphenol intake and health in large-scale epidemiological studies.     

Delay Equations with Non-negativity Constraints Driven by a Hölder Continuous Function of Order \beta \in \left(\frac13,\frac12\right)

In this note we prove an existence and uniqueness result of solution for multidimensional delay differential equations with normal reflection and driven by a Hölder continuous function of order \(\beta \in (\frac13,\frac12)\) . We also obtain a bound for the supremum norm of this solution. As an application, we get these results for stochastic differential equations driven by a fractional Brownian motion with Hurst parameter H \(\in (\frac13,\frac12)\) .     

Identification and Affinity-Quantification of ß-Amyloid and α-Synuclein Polypeptides Using On-Line SAW-Biosensor-Mass Spectrometry

Bioaffinity analysis using a variety of biosensors has become an established tool for detection and quantification of biomolecular interactions. Biosensors, however, are generally limited by the lack of chemical structure information of affinity-bound ligands. On-line bioaffinity-mass spectrometry using a surface-acoustic wave biosensor (SAW-MS) is a new combination providing the simultaneous affinity detection, quantification, and mass spectrometric structural characterization of ligands. We describe here an on-line SAW-MS combination for direct identification and affinity determination, using a new interface for MS of the affinity-isolated ligand eluate. Key element of the SAW-MS combination is a microfluidic interface that integrates affinity-isolation on a gold chip, in-situ sample concentration, and desalting with a microcolumn for MS of the ligand eluate from the biosensor. Suitable MS- acquisition software has been developed that provides coupling of the SAW-MS interface to a Bruker Daltonics ion trap-MS, FTICR-MS, and Waters Synapt-QTOF- MS systems. Applications are presented for mass spectrometric identifications and affinity (K_D) determinations of the neurodegenerative polypeptides, ß-amyloid (Aß), and pathophysiological and physiological synucleins (α- and ß-synucleins), two key polypeptide systems for Alzheimer’s disease and Parkinson’s disease, respectively. Moreover, first in vivo applications of αSyn polypeptides from brain homogenate show the feasibility of on-line affinity-MS to the direct analysis of biological material. These results demonstrate on-line SAW-bioaffinity-MS as a powerful tool for structural and quantitative analysis of biopolymer interactions.

Molecular clips with extended aromatic sidewalls as receptors for electron-acceptor molecules. Synthesis and NMR, photophysical, and electrochemical properties

We have synthesized molecular clips 1 comprising (i) two benzo[k]fluoranthene sidewalls and (ii) a dimethylene-connected benzene bridge that carries two acetoxy (1a), hydroxy (1b), or methoxy (1c) substituents in the para position. Their NMR spectra, single-crystal structures, and photophysical (fluorescence intensity, lifetime, depolarization) and electrochemical properties are discussed. For the purpose of comparison, similar compounds (2 and 3) containing only one benzo[k]fluoranthene unit have been prepared and studied. The strongly fluorescent clips 1 form stable complexes with electron-acceptor guests because of a highly negative electrostatic potential on the inner van der Waals surface of their cavity. The complexation constants in chloroform solution for a variety of guests, determined by NMR and fluorescence titration, are much larger than those of the corresponding anthracene and naphthalene clips (4 and 5), particularly in the case of extended aromatic guests. The effect of the substituents in the para position of the benzene spacer unit of clips 1 is discussed on the basis of the host-guest complex structures obtained by X-ray analysis and molecular mechanics simulations. In the case of 9-dicyanomethylene-2,4,7-trinitrofluorene (TNF) guest, complex formation with clip 1a causes dramatic changes in the photophysical and electrochemical properties: (i) a new charge-transfer band at 600 nm arises, (ii) a very efficient quenching of the strong benzo[k]fluoranthene fluorescence takes place, (iii) shifts of both the first oxidation (clip-centered) and reduction (TNF-centered) potentials are observed, and (iv) reversible disassembling of the complex can be obtained by electrochemical stimulation.     

Nanosized trigonal prismatic and antiprismatic CuII coordination cages based on tricarboxylate linkers

3D coordination cages have been synthesized via the supramolecular 3 + 2 self-assembly of macrocyclic dicopper molecular clips and tricarboxylate linkers, the nature of which allows the introduction of different functionalities to the 3D cages.