Toward Efficient and Stereoselective Aromatic and Dearomative Cope Rearrangements: Experimental and Theoretical Investigations of α-Allyl-α'-Aromatic γ-Lactone Derivatives.

The aromatic Cope rearrangement is an elusive transformation that has been the subject of a limited number of investigations compared to those seemingly close analogues, namely the Cope and aromatic Claisen rearrangement. Herein we report our investigations inspired by moderate success observed in the course of pioneering works. By careful experimental and theoretical investigations, we demonstrate that key substitutions on 1,5-hexadiene scaffold allow fruitful transformations. Especially, efficient functionalisation of the heteroaromatic rings results from the aromatic Cope rearrangement, while highly stereoselective interrupted aromatic Cope rearrangements highlight the formation of chiral compounds through a dearomative process.

New insight into atomic-level interpretation of interactions in molecules and reacting systems.

We hereby introduce the atomic degree of interaction (DOI), a new concept rooted in the electron density-based independent gradient model (IGM). Capturing any manifestation of electron density sharing around an atom, including covalent and non-covalent situations, this index reflects the attachment strength of an atom to its molecular neighbourhood. It is shown to be very sensitive to the local chemical environment of the atom. No significant correlation could be found between the atomic DOI and various other atomic properties, making this index a specific source of information. However, examining the simple H2 + H reacting system, a strong connection has been established between this electron density-based index and the scalar reaction path curvature, the cornerstone of the benchmark unified reaction valley approach (URVA). We observe that reaction path curvature peaks appear when atoms experience an acceleration phase of electron density sharing during the reaction, detected by peaks of the DOI second derivative either in the forward or reverse direction. This new IGM-DOI tool is only in its early stages, but it opens the way to an atomic-level interpretation of reaction phases. More generally, the IGM-DOI tool may also serve as an atomic probe of electronic structure changes of a molecule under the influence of physicochemical perturbations.

Deciphering the Role of Noncovalent Interactions in the Conformations of Dibenzo-1,5-dichalcogenocines.

This work reports a combined experimental and theoretical study on the new dibenzo-1,5-ditellurocine 2-Te in order to get an overview on the parameters controlling conformational change and to explain the differences with sulfur and selenium analogues. The preference of the boat conformer over the chair one is revealed by DFT calculations. For 2-Te, a ΔG value of about 3 kJ/mol was calculated, close to the value measured by NMR (5 kJ/mol). However, DFT calculations with implicit solvation effects could not clearly establish the presence of an intramolecular Te…HC noncovalent interaction (NCI), as observed in the solid state. The Independent Gradient Model (IGM) methodology discloses an existent but probably not sufficiently discriminating Te…HC NCI. It also confirms that van der Waals interactions between phenyl rings is a source of stabilization of the boat conformer. Furthermore, electrostatic potential analysis suggests that chalcogen bonds between Te σ-holes and solvent might play an important role.

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.

Pyridazinone derivatives as potential anti-inflammatory agents: synthesis and biological evaluation as PDE4 inhibitors.

Cyclic nucleotide phosphodiesterase type 4 (PDE4), which controls the intracellular level of cyclic adenosine monophosphate (cAMP), has aroused scientific attention as a suitable target for anti-inflammatory therapy of respiratory diseases. This work describes the development and characterization of pyridazinone derivatives bearing an indole moiety as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4-(5-methoxy-1H-indol-3-yl)-6-methylpyridazin-3(2H)-one possesses promising activity, and selectivity towards PDE4B isoenzymes and is able to regulate potent pro-inflammatory cytokine and chemokine production by human primary macrophages.

A Step toward the Quantification of Noncovalent Interactions in Large Biological Systems: The Independent Gradient Model-Extremely Localized Molecular Orbital Approach.

The independent gradient model (IGM) is a recent electron density-based computational method that enables to detect and quantify covalent and noncovalent interactions. When applied to large systems, the original version of the technique still relies on promolecular electron densities given by the sum of spherically averaged atomic electron distributions, which leads to approximate evaluations of the inter- and intramolecular interactions occurring in systems of biological interest. To overcome this drawback and perform IGM analyses based on quantum mechanically rigorous electron densities also for macromolecular systems, we coupled the IGM approach with the recently constructed libraries of extremely localized molecular orbitals (ELMOs) that allow fast and reliable reconstructions of polypeptide and protein electron densities. The validation tests performed on small polypeptides and peptide dimers have shown that the novel IGM-ELMO strategy provides results that are systematically closer to the fully quantum mechanical ones and outperforms the IGM method based on the crude promolecular approximation, but still keeping a quite low computational cost. The results of the test calculations carried out on proteins have also confirmed the trends observed for the IGM analyses conducted on small systems. This makes us envisage the future application of the novel IGM-ELMO approach to unravel complicated noncovalent interaction networks (e.g., in protein-protein contacts) or to rationally design new drugs through molecular docking calculations and virtual high-throughput screenings.

Novel approach to accurately predict bond strength and ligand lability in platinum-based anticancer drugs.

Prompted by the antineoplastic properties of cisplatin, a plethora of platinum(ii)-based complexes have been synthesized in the past decades. At present, their rational design is based on a number of structure-activity relationships involving the nature of the ligands initially coordinated to platinum(ii): either non-labile (acting as a carrier) or labile (undergoing substitution). The coordinate bond strength of the labile ligand plays a key role in the first step of the drug mechanism of action, i.e., the hydrolysis process, which is associated to the retention time of the medicine in the body. Therefore, an accurate determination of the metal-ligand bond strength becomes highly relevant as it will help the rational design of novel chemotherapeutic agents. Herein, we challenge the recently developed intrinsic bond strength index (IBSI) as a rapid and practical tool to assess the ligand lability in Pt(ii) complexes. In a first stage, given the importance of the trans-effect in synthetic strategies of cisplatin-based drugs, the effect of eleven trans-directing ligands T is quantified in two sets of complexes [Pt(NH3)2(H2O)T]n+ and [PtCl2(NH3)T]m+ where T = H2O, F-, NH3, Cl-, Br-, I-, SO32-, CH3-, CN-, CO, and H-. An essential outcome of this work is a novel index IBSItrans = IBSIσ + IBSIπ able to rank the directing ligands by their trans-effect according to their σ-donation and π-backbonding electronic contributions. In a second stage, we apply the IBSI score to a panel of eleven case studies, comprising mostly antineoplastic agents, such as cisplatin, carboplatin, lobaplatin etc., in order to quantify the coordinate bond strength of the ligands, providing insights about the hydrolysis process. The obtained results, in good agreement with experimental data and reported theoretical studies, demonstrate that the IBSI score is able to deliver a rapid and reliable picture of the coordinate bond strength, representing a chemically intuitive tool helpful for the development of novel anticancer agents prior to synthetic efforts.

Mechanistic insights into Smiles rearrangement. Focus on π-π stacking interactions along the radical cascade.

The synthesis of new arene and heteroarene scaffolds of therapeutic interest has generated a renewed interest in the domino radical cyclisation-Smiles. In this work we present a detailed mechanistic investigation of the radical version of a cascade involving a desulfonative Smiles rearrangement on an aromatic ring bearing a sulfonamide linker. Competing routes have been explored to characterize the molecular mechanism of the studied reaction. The knowledge gained from previous experimental observations is explained through the energy profile obtained by means of quantum mechanical calculations. This study answers questions about the rate determining step and the type of mechanism involved (two-step or concerted). Supplementary rate constant calculations as well as quantum molecular dynamics support experimental observations. An IGM-δg analysis performed along the reaction path unveils and quantifies an intramolecular π-π stacking interaction accelerating the reaction. This novel post processing IGM-δg tool based on the electron density, turns out to be useful to monitor and quantify specific intramolecular weak interactions along a reaction path from wave functions. From this mechanistic investigation it turns out that Smiles rearrangement here takes place in two steps rather than in a direct intramolecular radical substitution. Furthermore, we show that chain length effects must be taken into account in the functionalization of new sulfonylated derivatives subjected to this radical cascade, given their influence in the reaction rate.

New Way for Probing Bond Strength.

The covalent chemical bond is intimately linked to electron sharing between atoms. The recent independent gradient model (IGM) and its δg descriptor provide a way to quantify locally this electron density interpenetration from wavefunction calculations. Each bond has its own IGM-δgpair signature. The present work establishes for the first time a strong link between this bond signature and the physically grounded bond force constant concept. Analyzing a large set of compounds and bonds, the intrinsic bond strength index (IBSI) emerges from the IGM formulation. Our study shows that the IBSI does not belong to the class of conventional bond orders (like Mulliken, Wiberg, Mayer, delocalization index, or electron localization function-ELF), but is rather a new complementary index, related to the bond strength. A fundamental outcome of this research is a novel index allowing to range all two-center chemical bonds by their intrinsic strength in molecular situation. We believe that the IBSI is a powerful and robust tool for interpretation accessible to a wide community of chemists (organic, inorganic chemistry, including transition-metal complexes and reaction mechanisms).

Atomic Decomposition Scheme of Noncovalent Interactions Applied to Host-Guest Assemblies.

The design of novel stimuli-responsive supramolecular systems based on host-guest chemistry implies a thorough understanding of the noncovalent interactions involved. In this regard, some computational tools enabling the extraction of the noncovalent signatures from local descriptors based on the electron density have been previously proposed. Although very useful to detect the existence of such interactions, these analyses provide only a semi-quantitative description, which represents a limitation. In this work, we present a novel computational tool based on the local atomic descriptor IGM-δginter/At, which is able to decompose the fragment interaction into atomic contributions. Then, the role played by each atom in the formation of the host-guest assembly is quantified by an integrated Δginter/At score. Herein, we apply the IGM-Δginter/At approach to some challenging systems, including multimetallic arrays, buckycatchers, and organic assemblies. These systems exhibit unique structural features that make it difficult to determine the host/guest atoms that contribute the most to the guest encapsulation. Here, the Δginter/At score proves to be an appealing tool to shed light on the guest accommodation on a per-atom basis and could be useful in the rational design of more selective target agents. We strongly believe that this novel approach will be useful for experimental teams devoted to the synthesis of supramolecular systems based on host-guest chemistry.

Synthesis and biological evaluation of pyridazinone derivatives as potential anti-inflammatory agents.

Cyclic nucleotide phosphodiesterase type 4 (PDE4), that controls intracellular level of cyclic nucleotide cAMP, has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases. Here we describe the development of two families of pyridazinone derivatives as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4,5-dihydropyridazinone representatives possess promising activity, selectivity towards PDE4 isoenzymes and are able to reduce IL-8 production by human primary polymorphonuclear cells.

The Independent Gradient Model: A New Approach for Probing Strong and Weak Interactions in Molecules from Wave Function Calculations.

Extraction of the chemical interaction signature from local descriptors based on electron density (ED) is still a fruitful field of development in chemical interpretation. In a previous work that used promolecular ED (frozen ED), the new descriptor, δg , was defined. It represents the difference between a virtual upper limit of the ED gradient (∇ρIGM , IGM=independent gradient model) that represents a noninteracting system and the true ED gradient (∇ρ ). It can be seen as a measure of electron sharing brought by ED contragradience. A compelling feature of this model is to provide an automatic workflow that extracts the signature of interactions between selected groups of atoms. As with the noncovalent interaction (NCI) approach, it provides chemists with a visual understanding of the interactions present in chemical systems. ∇ρIGM is achieved simply by using absolute values upon summing the individual gradient contributions that make up the total ED gradient. Hereby, we extend this model to relaxed ED calculated from a wave function. To this end, we formulated gradient-based partitioning (GBP) to assess the contribution of each orbital to the total ED gradient. We highlight these new possibilities across two prototypical examples of organic chemistry: the unconventional hexamethylbenzene dication, with a hexa-coordinated carbon atom, and ß-thioaminoacrolein. It will be shown how a bond-by-bond picture can be obtained from a wave function, which opens the way to monitor specific interactions along reaction paths.

Development of the first model of a phosphorylated, ATP/Mg2+-containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design.

A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule. Then, different structural features (i.e. DFG motif, Mg2+ binding loop, activation loop, phosphorylation site and αC-helix region) were analysed for each trajectory to validate the aimed 2pBRAF_ATP model. Moreover, the structure and activating interactions of this 2pBRAF_ATP model were found to be in agreement with previously reported information. Finally, the model was further validated by means of a molecular docking study with our previously developed lead compound I confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies.

Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density.

An electron density (ED)-based methodology is developed for the automatic identification of intermolecular interactions using pro-molecular density. The expression of the ED gradient in terms of atomic components furnishes the basis for the Independent Gradient Model (IGM). This model leads to a density reference for non interacting atoms/fragments where the atomic densities are added whilst their interaction turns off. Founded on this ED reference function that features an exponential decay also in interference regions, IGM model provides a way to identify and quantify the net ED gradient attenuation due to interactions. Using an intra/inter uncoupling scheme, a descriptor (δginter) is then derived that uniquely defines intermolecular interaction regions. An attractive feature of the IGM methodology is to provide a workflow that automatically generates data composed solely of intermolecular interactions for drawing the corresponding 3D isosurface representations.

GPU accelerated implementation of NCI calculations using promolecular density.

The NCI approach is a modern tool to reveal chemical noncovalent interactions. It is particularly attractive to describe ligand-protein binding. A custom implementation for NCI using promolecular density is presented. It is designed to leverage the computational power of NVIDIA graphics processing unit (GPU) accelerators through the CUDA programming model. The code performances of three versions are examined on a test set of 144 systems. NCI calculations are particularly well suited to the GPU architecture, which reduces drastically the computational time. On a single compute node, the dual-GPU version leads to a 39-fold improvement for the biggest instance compared to the optimal OpenMP parallel run (C code, icc compiler) with 16 CPU cores. Energy consumption measurements carried out on both CPU and GPU NCI tests show that the GPU approach provides substantial energy savings. © 2017 Wiley Periodicals, Inc.

Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.

A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1.

Molecular properties affecting the adsorption coefficient of pesticides from various chemical families.

Forty pesticides were selected in function of their chemical families and their physico-chemical properties to represent a wide range of pesticide properties. Adsorption of these pesticides was studied on two soils by batch experiments. The two soils differed largely in organic matter and calcite contents. Distribution coefficient Kd was determined for each pesticide on the two soils. Adsorption was higher for the soil having the highest organic matter content and the lowest calcite content. In order to identify pesticide properties governing retention, eight molecular descriptors were determined from three-dimensional (3D) structure of molecules. Class-specific quantitative structure properties relationship (QSPR) soil adsorption models using one and two parameters were developed from experimental Kd. Three properties seemed to influence most retention of pesticides: hydrophobicity, solubility, and polarisability. Models combining these properties were suggested and discussed.

Switching invariant natural killer T (iNKT) cell response from anticancerous to anti-inflammatory effect: molecular bases.

Since the discovery in 1995 of α-galactosylceramide 1 (α-GalCer), also known as KRN7000,1 hundreds of compounds have been synthesized in order to activate invariant natural killer T (iNKT) cells. Such keen interest for this lymphocyte cell type is due to its ability to produce different cytokines that bias the immune response toward a Th1 or Th2 profile. Thus, an understanding of the immune polarization mechanism via iNKT activation may pave the way toward new therapeutics in various domains including cancer and infectious and autoimmune diseases. In this review, we propose an up-to-date analysis of iNKT activators associated with a structure-activity relationship (SAR) study aimed at complementing available reviews by highlighting molecular bases for a selective immune response.

KiSThelP: a program to predict thermodynamic properties and rate constants from quantum chemistry results.

Kinetic and Statistical Thermodynamical Package (KiSThelP) is a cross-platform free open-source program developed to estimate molecular and reaction properties from electronic structure data. To date, three computational chemistry software formats are supported (Gaussian, GAMESS, and NWChem). Some key features are: gas-phase molecular thermodynamic properties (offering hindered rotor treatment), thermal equilibrium constants, transition state theory rate coefficients (transition state theory (TST), variational transition state theory (VTST)) including one-dimensional (1D) tunnelling effects (Wigner, and Eckart) and Rice-Ramsperger-Kassel-Marcus (RRKM) rate constants, for elementary reactions with well-defined barriers. KiSThelP is intended as a working tool both for the general public and also for more expert users. It provides graphical front-end capabilities designed to facilitate calculations and interpreting results. KiSThelP enables to change input data and simulation parameters directly through the graphical user interface and to visually probe how it affects results. Users can access results in the form of graphs and tables. The graphical tool offers customizing of 2D plots, exporting images and data files. These features make this program also well-suited to support and enhance students learning and can serve as a very attractive courseware, taking the teaching content directly from results in molecular and kinetic modelling.

Molecular properties affecting the adsorption coefficient of phenylurea herbicides.

The adsorption of 12 pesticides of the phenylurea family was studied by batch experiments in order to determine the adsorption coefficient, K d. The study was conducted in two soils chosen for their differences in organic matter and calcite contents. K d pesticide adsorption coefficients were higher for soil S1 than for soil S2 due to the presence of a higher organic matter content and a lower calcite content in soil S1. To identify pesticide properties governing retention, 18 molecular descriptors were considered. Class-specific quantitative structure-property relationship (QSPR) soil sorption models using one, two, and three descriptors were developed from our experimental data using linear regressions. One of the aims of this work was to check whether QSPR models that did not include literature values of K ow were able to predict K d coefficients in satisfactory agreement with our experimental data. The influence of the level of theory in determining K ow and polarisability predictors on the predictive performance of the model was also examined by comparing quantum chemistry and empirical (QikProp) approaches. The one-descriptor model using "quantum" polarisability α was found to perform almost as well as or better than the other models.