Synthesis of a family of heterocyclic ligands derived from bisphenols: new flexible bridging ligands for use in metallosupramolecular chemistry

The preparations are described of 35 new bridging ligands from five bisphenols through coupling each with seven different heterocyclic units. X-ray crystal structures of five representative examples revealed different conformations in the solid state with the terminal nitrogen donors being separated by distances ranging from 8 to 23 Å.     

Exponential amplification by redox cross-catalysis and unmasking of doubly protected molecular probes

The strength of autocatalytic reactions lies in their ability to provide a powerful means of molecular amplification, which can be very useful for improving the analytical performances of a multitude of analytical and bioanalytical methods. However, one of the major difficulties in designing an efficient autocatalytic amplification system is the requirement for reactants that are both highly reactive and chemically stable in order to avoid limitations imposed by undesirable background amplifications. In the present work, we devised a reaction network based on a redox cross-catalysis principle, in which two catalytic loops activate each other. The first loop, catalyzed by H₂O₂, involves the oxidative deprotection of a naphthylboronate ester probe into a redox-active naphthohydroquinone, which in turn catalyzes the production of H₂O₂ by redox cycling in the presence of a reducing enzyme/substrate couple. We present here a set of new molecular probes with improved reactivity and stability, resulting in particularly steep sigmoidal kinetic traces and enhanced discrimination between specific and nonspecific responses. This translates into the sensitive detection of H₂O₂ down to a few nM in less than 10 minutes or a redox cycling compound such as the 2-amino-3-chloro-1,4-naphthoquinone down to 50 pM in less than 30 minutes. The critical reason leading to these remarkably good performances is the extended stability stemming from the double masking of the naphthohydroquinone core by two boronate groups, a counterintuitive strategy if we consider the need for two equivalents of H₂O₂ for full deprotection. An in-depth study of the mechanism and dynamics of this complex reaction network is conducted in order to better understand, predict and optimize its functioning. From this investigation, the time response as well as detection limit are found to be highly dependent on pH, nature of the buffer, and concentration of the reducing enzyme.

Reduction of the non-specific background in autocatalytic molecular amplifications by a double masking strategy.     

A direct sensitized fluorimetric determination of 5,10,15,20-tetra(m-hydroxyphenyl)chlorin [m-THPC (Foscan)] in human plasma using a cyclodextrin inclusion complex.

The 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (m-THPC) (Foscan) is a photosensitizer used in the photodynamic therapy (PDT) of cancers which is currently under clinical trial. The formation of a m-THPC inclusion complex with dimethyl-beta-cyclodextrin (Me-beta-CD) in solution was demonstrated on the basis of circular dichroism experiments. A 1:2 complex stoichiometry was found and an inclusion constant beta 2 = 2.8(+/- 0.4) x 10(10) M-2 was determined. The formation of such a complex was shown to enhance the m-THPC fluorescence intensity. It could be exploited to improve the sensitivity of the direct m-THPC detection in human plasma. Optimization of the operating conditions shows that the best results were obtained by the addition of 100 microL of a concentrated Me-beta-CD solution (3.2 x 10(-2) M) to 1 mL plasma samples. Compared to the standard conditions, a 90% increase in sensitivity was obtained. The proposed analytical method which showed a linear response function [0-300 ng mL-1 (440 pM)] and a low limit of detection [1.5 ng mL-1 (2 pM) (S/N = 3)] appears, especially due to the absence of metabolism, a simple and specific method suitable for pharmacokinetics studies in patients.     

Rapid analysis of long‐chain glycolipids in heterocystous cyanobacteria using high‐performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry

Under nitrogen‐depleted conditions, N₂‐fixing cyanobacteria of the order Nostocales and Stigonematales differentiate vegetative cells into heterocysts. The cell envelope of these specialized cells contains unique glycolipids, consisting of a sugar moiety glycosidically bound to long‐chain diols, triols and hydroxyketones. Only few reports have been published on these glycolipids in cultured cyanobacteria and none has reported them in natural environments. Here we show that heterocyst glycolipids can be rapidly and sensitively analyzed using high‐performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC/ESI‐MS²). Positive ion mass spectra of the glycolipids consisted of protonated molecules and diagnostic product ions, indicating losses of sugar groups as well as hydroxyl and carbonyl functionalities from an alkyl chain. Using this method, heterocyst glycolipids were for the first time identified in a natural ecosystem, i.e., a microbial mat from the North Sea barrier island Schiermonnikoog, The Netherlands. This technique will facilitate the quick screening of cyanobacterial cultures and natural environments for the presence of heterocyst glycolipids, which may aid in assessing the role of heterocystous cyanobacteria in the global nitrogen cycle. Copyright © 2009 John Wiley & Sons, Ltd.     

Mixed-mode oscillations and slow manifolds in the self-coupled FitzHugh-Nagumo system

We investigate the organization of mixed-mode oscillations in the self-coupled FitzHugh-Nagumo system. These types of oscillations can be explained as a combination of relaxation oscillations and small-amplitude oscillations controlled by canard solutions that are associated with a folded singularity on a critical manifold. The self-coupled FitzHugh-Nagumo system has a cubic critical manifold for a range of parameters, and an associated folded singularity of node-type. Hence, there exist corresponding attracting and repelling slow manifolds that intersect in canard solutions. We present a general technique for the computation of two-dimensional slow manifolds (smooth surfaces). It is based on a boundary value problem approach where the manifolds are computed as one-parameter families of orbit segments. Visualization of the computed surfaces gives unprecedented insight into the geometry of the system. In particular, our techniques allow us to find and visualize canard solutions as the intersection curves of the attracting and repelling slow manifolds.     

Photofragment imaging study of the CH2CCH2OH radical intermediate of the OH+allene reaction

These velocity map imaging experiments characterize the photolytic generation of one of the two radical intermediates formed when OH reacts via an addition mechanism with allene. The CH2CCH2OH radical intermediate is generated photolytically from the photodissociation of 2-chloro-2-propen-1-ol at 193 nm. Detecting the Cl atoms using [2+1] resonance-enhanced multiphoton ionization evidences an isotropic angular distribution for the Cl+CH2CCH2OH photofragments, a spin-orbit branching ratio for Cl(2P1/2):Cl(2P3/2) of 0.28, and a bimodal recoil kinetic energy distribution. Conservation of momentum and energy allows us to determine from this data the internal energy distribution of the nascent CH2CCH2OH radical cofragment. To assess the possible subsequent decomposition pathways of this highly vibrationally excited radical intermediate, we include electronic structure calculations at the G3//B3LYP level of theory. They predict the isomerization and dissociation transition states en route from the initial CH2CCH2OH radical intermediate to the three most important product channels for the OH+allene reaction expected from this radical intermediate: formaldehyde+C2H3, H+acrolein, and ethene+CHO. We also calculate the intermediates and transition states en route from the other radical adduct, formed by addition of the OH to the center carbon of allene, to the ketene+CH3 product channel. We compare our results to a previous theoretical study of the O+allyl reaction conducted at the CBS-QB3 level of theory, as the two reactions include several common intermediates.     

Hydrogen tunneling steps in cyclooxygenase-2 catalysis

Cyclooxygenases-1 and -2 are tyrosyl radical (Y·)-utilizing hemoproteins responsible for the biosynthesis of lipid-derived autocoids. COX-2, in particular, is a primary mediator of inflammation and believed to be up-regulated in many forms of cancer. Described here are first-of-a-kind studies of COX-2-catalyzed oxidation of the substrate analogue linoleic acid. Very large (≥20) temperature-independent deuterium kinetic isotope effects (KIEs) on the rate constant for enzyme turnover were observed, due to hydrogen atom abstraction from the bisallylic C-H(D) of the fatty acid. The magnitude of the KIE depends on the O(2) concentration, consistent with reversible H/D tunneling mediated by the catalytic Y·. At physiological levels of O(2), retention of the hydrogen initially abstracted by the catalytic tyrosine results in strongly temperature-dependent KIEs on O-H(D) homolysis, also characteristic of nuclear tunneling.     

Canard cycles in aircraft ground dynamics

The loss of lateral stability of an aircraft turning on the ground is associated with a rapid transition from small-amplitude oscillations to large-amplitude relaxation oscillations over a very small parameter range. This phenomenon is shown to correspond to a canard explosion, which is known to be an important feature of systems that exhibit a separation of time scales. While the industry-tested model of aircraft ground dynamics that we consider does not feature an explicit splitting of time scales, we show that, locally near the transition from stable turning to laterally unstable behaviour, the forward speed of the aircraft acts as a slow variable. The associated family of canard cycles is identified, and the canard explosion is shown to be directly related to the successive saturation of tyre forces at the two main landing gears. We present a canonical two-dimensional slow–fast vector field model that captures the key features of this type of canard explosion; it differs from the canard explosion in the archetypical Van der Pol system in terms of the shape of the associated critical manifold.