Experimental and computational insights into the mechanism of the copper(I)-catalysed sulfonylative Suzuki-Miyaura reaction

A mechanistic study into the copper(I)-catalysed sulfonylative Suzuki-Miyaura reaction, incorporating sulfur dioxide, is described. Utilising spectroscopic and computational techniques, an exploration into the individual components of the competing catalytic cycles is delineated, including identification of the resting state catalyst, transmetalation of arylboronic acid onto copper(I), the sulfur dioxide insertion process, and the oxidative addition of aryl halide to CuI. Studies also investigated prominent side-reactions which were uncovered, including a competing copper(II)-catalysed mechanism. This led to an additional proposed and connected CuI/CuII/CuIII catalytic cycle to account for by-product formation

Profiling sulfur(VI) fluorides as reactive functionalities for chemical biology tools and expansion of the ligandable proteome

Here, we report a comprehensive profiling study of sulfur(VI) fluorides (SVI-F) in the context of multiple chemical biology applications and illustrate that these motifs present an exciting opportunity to develop tools for a wide scope of protein targets. SVI-Fs are reactive functionalities that offer utility for targeting almost any protein, as they can modify multiple residues including Lys, Tyr, His and Ser. A panel of SVI-F functionalities were studied with respect to hydrolytic stability and reactivity with nucleophilic amino acids. Subsequently, the reactivity of SVI-Fs with CAII and kinase proteins was investigated, in the context of both fragment binders and optimized probes. Finally, the performance of the SVI-F panel in chemoproteomic workflows was analyzed. The studies provided an in-depth understanding of the hydrolytic stability, protein reactivity and chemoproteomic utility of SVI-F functionalities that are suitable for direct incorporation into chemical tools. Such insights offer a valuable guide for the prospective design of SVI-F-containing ligands for various chemical biology workflows and demonstrate the wide range of proteins that SVI-Fs can capture, thus highlighting the opportunity for SVI-Fs to expand the liganded proteome

Theoretical investigation of NpC, NpC2 and NpC4 molecules

The electronic structure and geometrical parameters of ground and low-lying excited states of neptunium mono-, di- and tetracarbides were investigated by relativistic CASSCF/CASPT2 multireference calculations with an all-electron basis set as well as with density functional theory (B3LYP) in conjunction with relativistic pseudopotentials. The CASPT2 calculations were extended with complete active space state interaction (CASSI) calculations in order to include spin-orbit coupling and calculate the absorption electronic spectra. In case of the actinide monocarbides vibrational frequencies were calculated both for the lowest-energy spin-free and spin-orbit states. For di- and tetracarbides infrared and Raman spectral characteristics were obtained using DFT calculations. For dicarbides two structures were investigated: the symmetric triangular (Np-C2) structure including an acetylide moiety which was found to be the ground state and the symmetric linear (CNpC) structure. In case of tetracarbides fourteen different structures were investigated. The ground state was found to be a planar fan-like structure where neptunium is connected to a bent C4 moiety. The found structures agree well with the previous investigations of other actinide carbides (Th, U, Pu, Am). The bonding characteristics of the low-energy structures were analysed on the basis of valence molecular orbitals.JRC.E.3-Materials researc

Theoretical study of actinide monocarbides (ThC, UC, PuC, and AmC)

A study of four representative actinide monocarbides, ThC, UC, PuC, and AmC, has been performed with relativistic quantum chemical calculations. The two applied methods were multireference com- plete active space second-order perturbation theory (CASPT2) including the Douglas-Kroll-Hess Hamiltonian with all-electron basis sets and density functional theory with the B3LYP exchange- correlation functional in conjunction with relativistic pseudopotentials. Beside the ground electronic states, the excited states up to 17 000 cm 1 have been determined. The molecular properties explored included the ground-state geometries, bonding properties, and the electronic absorption spectra. According to the occupation of the bonding orbitals, the calculated electronic states were classified into three groups, each leading to a characteristic bond distance range for the equilibrium geometry. The ground states of ThC, UC, and PuC have two doubly occupied π orbitals resulting in short bond distances between 1.8 and 2.0 Å, whereas the ground state of AmC has significant occupation of the antibonding orbitals, causing a bond distance of 2.15 Å

bbSelect : an open-source tool for performing a 3D pharmacophore-driven diverse selection of R-groups

The design of compounds during hit-to-lead often seeks to explore a vector from a core scaffold to form additional interactions with the target protein. A rational approach to this is to probe the region of a protein accessed by a vector with a systematic placement of pharmacophore features in 3D, particularly when bound structures are not available. Herein, we present bbSelect, an open-source tool built to map the placements of pharmacophore features in 3D Euclidean space from a library of R-groups, employing partitioning to drive a diverse and systematic selection to a user-defined size. An evaluation of bbSelect against established methods exemplified the superiority of bbSelect in its ability to perform diverse selections, achieving high levels of pharmacophore feature placement coverage with selection sizes of a fraction of the total set and without the introduction of excess complexity. bbSelect also reports visualizations and rationale to enable users to understand and interrogate results. This provides a tool for the drug discovery community to guide their hit-to-lead activities