Addition of Vindoline to p-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations

Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This “windshield wiper” effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 μM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.

Fate of the Gas-Phase Reaction Between Oxirane and the CN Radical in Interstellar Conditions

The escalating identification of new complex molecules in the interstellar medium claims for potential formation routes of such species. In this regard, the present work considers the reaction between oxirane and the CN radical as a feasible formation mechanism of species having the C3H3NO molecular formula. Indeed, the compounds of this family are elusive in the interstellar medium and suggestions on which species could be formed at low temperature and low pressure conditions might aid their discovery. The c-C2H4O + CN reaction has been investigated from the thermodynamic and kinetic points of view. The thermodynamic has been studied by means of a double-hybrid density functional and revealed the presence of several mechanisms submerged with respect to the reactants energy, with the potential formation of oxazole and cyanoacetaldehyde. However, the kinetic results suggest that the main reaction pathway is the H-extraction, leading to 2-oxiranyl radical and HCN. The formation of cyanoacetaldehyde + H and of H2CCN + H2CO is also possible with smaller rate constants, while the production of oxazole is negligible due to the presence of a high energy barrier.

Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes

Tissue-resident intestinal intraepithelial T lymphocytes (T-IEL) patrol the gut and have important roles in regulating intestinal homeostasis. T-IEL include both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural IEL, which are developmentally targeted to the intestine. While the processes driving T-IEL development have been elucidated, the precise roles of the different subsets and the processes driving activation and regulation of these cells remain unclear. To gain functional insights into these enigmatic cells, we used high-resolution, quantitative mass spectrometry to compare the proteomes of induced T-IEL and natural T-IEL subsets, with naive CD8+ T cells from lymph nodes. This data exposes the dominant effect of the gut environment over ontogeny on T-IEL phenotypes. Analyses of protein copy numbers of >7000 proteins in T-IEL reveal skewing of the cell surface repertoire towards epithelial interactions and checkpoint receptors; strong suppression of the metabolic machinery indicating a high energy barrier to functional activation; upregulated cholesterol and lipid metabolic pathways, leading to high cholesterol levels in T-IEL; suppression of T cell antigen receptor signalling and expression of the transcription factor TOX, reminiscent of chronically activated T cells. These novel findings illustrate how T-IEL integrate multiple tissue-specific signals to maintain their homeostasis and potentially function.

A fundamental viewpoint on the hydrogen spillover phenomenon of electrocatalytic hydrogen evolution

Hydrogen spillover phenomenon of metal-supported electrocatalysts can significantly impact their activity in hydrogen evolution reaction (HER). However, design of active electrocatalysts faces grand challenges due to the insufficient understandings on how to overcome this thermodynamically and kinetically adverse process. Here we theoretically profile that the interfacial charge accumulation induces by the large work function difference between metal and support (∆Φ) and sequentially strong interfacial proton adsorption construct a high energy barrier for hydrogen transfer. Theoretical simulations and control experiments rationalize that small ∆Φ induces interfacial charge dilution and relocation, thereby weakening interfacial proton adsorption and enabling efficient hydrogen spillover for HER. Experimentally, a series of Pt alloys-CoP catalysts with tailorable ∆Φ show a strong ∆Φ-dependent HER activity, in which PtIr/CoP with the smallest ∆Φ = 0.02 eV delivers the best HER performance. These findings have conclusively identified ∆Φ as the criterion in guiding the design of hydrogen spillover-based binary HER electrocatalysts.

Boosting proton reduction via isolated Cu atoms in Bi lattice for efficient electroreduction of CO2 to formate

Current Bi-based catalysts suffer from low current density for electroreduction of CO2 to formate due to the high energy barrier of H+ reduction to *H on Bi sites. Here we report a unique BiCu single-atom alloy catalyst (SAAC) that can deliver a ultrahigh formate partial current density (jformate) of 434 mA cm–2, the highest among the reported Bi-based electrocatalysts to date, with a formate Faradaic efficiency (FEformate) of 96.5% at –0.55 V (vs. RHE) in a flow cell, while BiCu alloy catalyst containing Cu nanoclusters can only deliver a jformate of 48.5 mA cm–2 with a FEformate of 37.3% under an identical condition. Mechanism investigations reveal that the isolated single-atom Cu in BiCu SAAC can dramatically reduce the energy barrier of H+ reduction to *H on Cu site for boosting the reduction of CO2 to formate. Our work provides a new strategy for engineering unfavourable energy barrier of electrocatalysts to promote CO2 reduction.

Rh(I)-Catalyzed Enantioselective Cyclization of Enyne through Site-Selective C(sp3)-H Bond Activation Triggered by Formation of Rhodacycle

Rh(I)-catalyzed enantioselective cyclization of enyne through C(sp3)-H bond activation was investigated. It was found that the cyclization of enyne having a t-butyl moiety on the alkene afforded a spirocyclic compound (up to 92% ee), while the cyclization of enyne having an i-propyl or an ethyl group on the alkene gave a cyclic diene (up to 98% ee). Furthermore, an intermolecular competition reaction using a deuterium-labeled substrate revealed that C(sp3)-H bond activation was one of the key steps, having a high energy barrier, in this cyclization.

Tissue environment, not ontogeny, defines intestinal intraepithelial T lymphocytes

Tissue-resident intestinal intraepithelial T lymphocytes (T-IEL) patrol the gut and have important roles in regulating intestinal homeostasis. T-IEL include both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural IEL, which are developmentally targeted to the intestine. While the processes driving T-IEL development have been elucidated, the precise roles of the different subsets and the processes driving activation and regulation of these cells remain unclear. To gain functional insights into these enigmatic cells, we used high-resolution, quantitative mass spectrometry to investigate the proteomic landscape of the main T-IEL populations in the gut. Comparing the proteomes of induced T-IEL and natural T-IEL subsets, with naive CD8+ T cells from lymph nodes exposes the dominant effect of the gut environment over ontogeny on T-IEL phenotypes. Analyses of protein copy numbers of >7000 proteins in T-IEL reveal skewing of the cell surface repertoire towards epithelial interactions and checkpoint receptors; strong suppression of the metabolic machinery indicating a high energy barrier to functional activation; and changes in T cell antigen receptor signalling pathways reminiscent of chronically activated T cells. These novel findings illustrate how multiple input signals need to be integrated to regulate T-IEL function.

Electrochromic shift supports the membrane destabilization model of Tat-mediated transport and shows ion leakage during Sec transport

The mechanism and pore architecture of the Tat complex during transport of folded substrates remain a mystery, partly due to rapid dissociation after translocation. In contrast, the proteinaceous SecY pore is a persistent structure that needs only to undergo conformational shifts between “closed” and “opened” states when translocating unfolded substrate chains. Where the proteinaceous pore model describes the SecY pore well, the toroidal pore model better accounts for the high-energy barrier that must be overcome when transporting a folded substrate through the hydrophobic bilayer in Tat transport. Membrane conductance behavior can, in principle, be used to distinguish between toroidal and proteinaceous pores, as illustrated in the examination of many antimicrobial peptides as well as mitochondrial Bax and Bid. Here, we measure the electrochromic shift (ECS) decay as a proxy for conductance in isolated thylakoids, both during protein transport and with constitutively assembled translocons. We find that membranes with the constitutively assembled Tat complex and those undergoing Tat transport display conductance characteristics similar to those of resting membranes. Membranes undergoing Sec transport and those with the substrate-engaged SecY pore result in significantly more rapid electric field decay. The responsiveness of the ECS signal in membranes with active SecY recalls the steep relationship between applied voltage and conductance in a proteinaceous pore, while the nonaccelerated electric field decay with both Tat transport and the constitutive Tat complex under the same electric field is consistent with the behavior of a toroidal pore.