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Epothilones are 16‐membered macrolides that act as microtubule‐targeting agents to tackle cancer. Many synthetic analogues have been investigated for their activity, yet often based on macrolide structures. A notable exception is Ixabepilone, an azalide whose metabolic stability and pharmacokinetics are significantly improved. Exploiting the amide‐triazole bioisosterism, in this work we report the synthesis of the first generation of epothilones lacking the macrolide or azalide structure, with the ester or amide linkage replaced by a triazole unit. Together with the synthesis of this new analogue, computational and biological evaluations have been performed too. [ABSTRACT FROM AUTHOR]

A dimeric cyclic cysteine analogue, i.e. (1R,1′R,2R,2′R)‐2,2′‐disulfanediylbis (aminocyclohexane‐1‐carboxylic acid), was used as a constrained unnatural amino acid and as a folding inducer in ultra‐short Leu‐Val‐containing peptide. Our results showed that both free dimer amino acid L1 and its peptide derivative L2 are able to chelate Cu(II). The obtained complexes resulted to be catalytically active in Michael addition reaction of nitromethane on different types of chalcones. L1‐Cu(II) was shown more reactive in terms of conversion, while, in neat conditions, L2‐Cu(II) allows to obtain an interesting 60 % e.e. on pyridine chalcone. [ABSTRACT FROM AUTHOR]

Microanalysis techniques based on resonance Raman and reflection visible spectroscopy have been applied to the characterization of pigments responsible for the blue or violet coloration in flowers; in particular of Lobelia erinus, Campanula portenschlagiana, Cineraria, Viola tricolor, Anemone coronaria, Agapanthus, Platycodon, Salvia farinacea, Plumbago capensis, Ceratostigma plumbaginoides, Commelina communis and Salvia patens. The spectroscopic methods were applied both in vivo on the flower petals and in vitro on extracts obtained through a procedure based on SPE (solid-phase extraction) optimized for minimal quantities of vegetable raw material. Different patterns obtained for the Raman spectra have been correlated, also on the basis of density functional theory (DFT) calculations, with different schemes of substitution of the benzopyrilium nucleus of the anthocyanins and with various possible forms of copigmentation responsible for the stabilization of the blue color. The results obtained were verified by comparison with the analysis of the extracts by HPLC-ESI-MS (liquid chromatography-electrospray ionization-mass spectrometry). [ABSTRACT FROM AUTHOR]

Microtubules are highly dynamic polymers of α,β-tubulin dimers which play an essential role in numerous cellular processes such as cell proliferation and intracellular transport, making them an attractive target for cancer and neurodegeneration research. To date, a large number of known tubulin binders were derived from natural products, while only one was developed by rational structure-based drug design. Several of these tubulin binders show promising in vitro profiles while presenting unacceptable off-target effects when tested in patients. Therefore, there is a continuing demand for the discovery of safer and more efficient tubulin-targeting agents. Since tubulin structural data is readily available, the employment of computer-aided design techniques can be a key element to focus on the relevant chemical space and guide the design process. Due to the high diversity and quantity of structural data available, we compiled here a guide to the accessible tubulin-ligand structures. Furthermore, we review different ligand and structure-based methods recently used for the successful selection and design of new tubulin-targeting agents. [ABSTRACT FROM AUTHOR]

Maytansinoids are a successful class of natural and semisynthetic tubulin binders, known for their potent cytotoxic activity. Their wider application as cytotoxins and chemical probes to study tubulin dynamics has been held back by the complexity of natural product chemistry. Here we report the synthesis of long‐chain derivatives and maytansinoid conjugates. We confirmed that bulky substituents do not impact their high activity or the scaffold's binding mode. These encouraging results open new avenues for the design of new maytansine‐based probes. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 Mpro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of Mpro is characterized by the presence of a catalytic Cys145 which carries out the hydrolytic activity of the enzyme. As a consequence, several Mpro inhibitors have been proposed to date in order to fight the COVID-19 pandemic. In our work, we designed, synthesized and biologically evaluated MPD112, a novel inhibitor of SARS-CoV-2 Mpro bearing a trifluoromethyl diazirine moiety. MPD112 displayed in vitro inhibition activity against SARS-CoV-2 Mpro at a low micromolar level (IC50 = 4.1 μM) in a FRET-based assay. Moreover, an inhibition assay against PLpro revealed lack of inhibition, assuring the selectivity of the compound for the Mpro. Furthermore, the target compound MPD112 was docked within the binding site of the enzyme to predict the established intermolecular interactions in silico. MPD112 was subsequently tested on the HCT-8 cell line to evaluate its effect on human cells' viability, displaying good tolerability, demonstrating the promising biological compatibility and activity of a trifluoromethyl diazirine moiety in the design and development of SARS-CoV-2 Mpro binders. [ABSTRACT FROM AUTHOR]

Umami taste is elicited predominantly by monosodium glutamate (MSG) and purine 5'‐ribonucleotides, in particular guanosine and inosine 5'‐monophosphates (GMP and IMP). A significant peculiarity of umami compounds is their capacity to interact synergistically. A possible explanation of such phenomenon is that both l‐glutamate and ribonucleotides may interact simultaneously with the "Venus flytrap" domain of T1R1/T1R3 umami receptor, but at different sites. Starting from this model, we reasoned that hybrid compounds, containing the two umami moieties covalently connected through flexible linkers of variable length, could be able to reach both umami receptor sites through a single molecule, thus giving an insight into the mechanism of synergism. MD simulations suggested that a chain of at least eight carbon atoms is requested to allow the interaction of both l‐glutamate and 5'‐ribonucleotide with their respective binding sites. We report here the synthesis of such hybrids starting from 2',3'‐O‐isopropylidene‐5'‐O‐t‐butyldimethylsilylguanosine. [ABSTRACT FROM AUTHOR]

Molecular similarity is an impressively broad topic with many implications in several areas of chemistry. Its roots lie in the paradigm that 'similar molecules have similar properties'. For this reason, methods for determining molecular similarity find wide application in pharmaceutical companies, e.g., in the context of structure-activity relationships. The similarity evaluation is also used in the field of chemical legislation, specifically in the procedure to judge if a new molecule can obtain the status of orphan drug with the consequent financial benefits. For this procedure, the European Medicines Agency uses experts' judgments. It is clear that the perception of the similarity depends on the observer, so the development of models to reproduce the human perception is useful. In this paper, we built models using both 2D fingerprints and 3D descriptors, i.e., molecular shape and pharmacophore descriptors. The proposed models were also evaluated by constructing a dataset of pairs of molecules which was submitted to a group of experts for the similarity judgment. The proposed machine-learning models can be useful to reduce or assist human efforts in future evaluations. For this reason, the new molecules dataset and an online tool for molecular similarity estimation have been made freely available. [ABSTRACT FROM AUTHOR]

Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by the intriguing structure of the macrocycle and the success in targeted cancer therapy of the derivatives, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives with novel modifications of the maytansine scaffold. We characterized these molecules by docking studies, by a comprehensive biochemical evaluation, and by determination of their crystal structures in complex with tubulin. The results shed further light on the intriguing chemical behavior of maytansinoids and confirm the relevance of this peculiar scaffold in the scenario of tubulin binders. [ABSTRACT FROM AUTHOR]

A QTAIM and IQA investigation on model compounds of two isostructural AgI and CuI coordination polymers (CPs) based on cyclic triimidazole (L), i.e. the [MIL]n 1D double‐stranded stair chain and the [MClL]n 3D network (M = Cu, Ag), has allowed light to be shed on the different emissive behaviour associated with the two metal ions. According to a previously reported investigation [Malpicci et al. (2021). Inorg. Chem. Front.8, 1312–1323], AgI CPs showed both fluorescence and multiple ligand‐centred room‐temperature phosphorescences, whereas CuI CPs displayed non‐thermally equilibrated halogen and metal‐to‐ligand charge transfer and two ligand‐centred phosphorescences, the latter observed only by their selective activation. Analysis of both local and integral QTAIM descriptors, including delocalization indices and source function, of the Ag—N and Cu—N bonds reveals a higher covalent and local character for the latter, explaining the greater metal–ligand electronic communication observed for the Cu compounds. Moreover, IQA investigation shows that the Cu—N bond is characterized by higher interaction energy, due to both higher electrostatic and exchange‐correlation contributions. Analysis on the M—X (M = Ag, Cu; X = I, Cl) bonds, also present in these structures, highlights a much higher covalent and local character with respect to the M—N bonds. [ABSTRACT FROM AUTHOR]

Two FtsZ targeting cyclic peptides 1 (Ac-[Orn-Leu-Met-Asp]-Ala-Phe-Arg-Ser-NH2) and 2 (Ac-Ser-Leu-Met-[Asp-Ala-Phe-Arg-Orn]-NH2) were found to be inhibitors of FtsZ polymerization, that makes them excellent starting point for the future development of a new class of antimicrobials. We investigated their solution structure by means of nuclear magnetic resonance (NMR) and molecular dynamic simulations (MD). Deep analysis of 2D NMR spectra (COSY, TOCSY and NOESY), recorded in DMSO-d6, allowed the assignments of all peptide signals and suggested the presence of strong turn structures. We also noticed that the guanidine group of Arg significantly affects the spectral properties and the chromatographic behavior of these peptides depending on whether it makes part of the cycle or not. MD simulations allowed to investigate the conformational preference of the two cyclic peptides and to associate diversity in their structure and dynamics to their different behavior. In particular, peptide 1 showed enhanced flexibility and structural variance with respect to peptide 2. [ABSTRACT FROM AUTHOR]

A detailed Valence Bond‐Spin Coupled analysis of a series of halogenated molecules is here reported, allowing to get a rigorous ab initio demonstration of the qualitative models previously proposed to explain the origin of halogen bonding. The concepts of σ‐hole and negative belt observed around the halogen atoms in the electrostatic potential maps are here interpreted by analysis of the relevant Spin Coupled orbitals. [ABSTRACT FROM AUTHOR]

Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function "one pot" reacts with the carboxylic group of N-Fmoc-protected amino acids leading to amidino depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction. [ABSTRACT FROM AUTHOR]

One of the well‐established methods of modern quantum crystallography is undoubtedly the X‐ray constrained wavefunction (XCW) approach, a technique that enables the determination of wavefunctions which not only minimize the energy of the system under examination, but also reproduce experimental X‐ray diffraction data within the limit of the experimental errors. Initially proposed in the framework of the Hartree–Fock method, the strategy has been gradually extended to other techniques of quantum chemistry, but always remaining limited to a single‐determinant ansatz for the wavefunction to extract. This limitation has been recently overcome through the development of the novel X‐ray constrained spin‐coupled (XCSC) approach [Genoni et al. (2018). Chem. Eur. J.24, 15507–15511] which merges the XCW philosophy with the traditional spin‐coupled strategy of valence bond theory. The main advantage of this new technique is the possibility of extracting traditional chemical descriptors (e.g. resonance structure weights) compatible with the experimental diffraction measurements, without the need to introduce information a priori or perform analyses a posteriori. This paper provides a detailed theoretical derivation of the fundamental equations at the basis of the XCSC method and also introduces a further advancement of its original version, mainly consisting in the use of molecular orbitals resulting from XCW calculations at the Hartree–Fock level to describe the inactive electrons in the XCSC computations. Furthermore, extensive test calculations, which have been performed by exploiting high‐resolution X‐ray diffraction data for salicylic acid and by adopting different basis sets, are presented and discussed. The computational tests have shown that the new technique does not suffer from particular convergence problems. Moreover, all the XCSC calculations provided resonance structure weights, spin‐coupled orbitals and global electron densities slightly different from those resulting from the corresponding unconstrained computations. These discrepancies can be ascribed to the capability of the novel strategy to capture the information intrinsically contained in the experimental data used as external constraints. [ABSTRACT FROM AUTHOR]

A sequence of seven reactions (stereocontrolled allylation, Mitsunobu reaction, ring closing metathesis, and amino/amido intramolecular nucleophilic addition) efficiently convert the inexpensive starting 2‐piperidine ethanol into a small library of enatiomerically pure nitrogen containing compounds characterized by three new scaffolds that present a relevant diversity. This simple approach encroaches the further exploration of the chemical space. [ABSTRACT FROM AUTHOR]

Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin‐inspired derivatives. The modest bioactivity and the apparent absence of interaction with α‐tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α‐tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p‐Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules. Impact of the linker: Four different hybrid compounds have been efficiently synthesized by conjugation of N‐deacetyl‐10‐thiocolchicine with pironetin‐inspired derivatives. The study better clarifies the design of bivalent compounds for targeting hetero microtubules. [ABSTRACT FROM AUTHOR]

Invited for the cover of this issue are the groups of Professors Passarella and Pieraccini at the University of Milan, in collaboration with some of the members of TubInTrain consortium. The image depicts work with the elements of nature, in particular the destabilising effect of maytansinol (the constellation) on microtubules (the trees). Read the full text of the article at 10.1002/chem.202203431. [ABSTRACT FROM AUTHOR]

Invited for the cover of this issue are the groups of Professors Passarella and Pieraccini at the University of Milan, in collaboration with some of the members of TubInTrain consortium. The image depicts work with the elements of nature, in particular the destabilising effect of maytansinol (the constellation) on microtubules (the trees). Read the full text of the article at 10.1002/chem.202203431. [ABSTRACT FROM AUTHOR]

The X‐ray constrained wavefunction (XCW) approach is a reliable and widely used method of quantum crystallography that allows the determination of wavefunctions compatible with X‐ray diffraction data. So far, all the existing XCW techniques have been developed in the framework of molecular orbital theory and, consequently, provide only pictures of the "experimental" electronic structures that are far from the traditional chemical perception. Here a new strategy is proposed that, by combining the XCW philosophy with the spin‐coupled method of valence bond theory, enables direct extraction of traditional chemical information (e.g. weights of resonance structures) from X‐ray diffraction measurements. Preliminary results have shown that the new technique is really able to efficiently capture the effects of the crystal environment on the electronic structure, and can be considered as a new useful tool to perform chemically sound analyses of the X‐ray diffraction data. From X‐ray diffraction to resonance structures weights. A new quantum crystallographic method that enables taking into account the X‐ray diffraction data in full Valence Bond calculations is proposed. Exploiting the new technique, insights into the electron distributions around each atomic center and, particularly, into the weights of resonance structures can be directly obtained from usual X‐ray diffraction measurements. [ABSTRACT FROM AUTHOR]

The Ebola viral Protein 24 (VP24) inhibits interferon signaling through its interaction with the human protein Karyopherin, thus impairing the immune response of the host against the infection and increasing its rate of diffusion into the organism and its lethality. This makes VP24 a potential pharmacological target, as the inhibition of its interaction with Karyopherin could reduce Ebola virulence. In this work, we carried out an atomic level study of the network of interactions between VP24 and Karyopherin using molecular dynamics and computational alanine scanning. Modeling the VP24–Karyopherin complex allowed us to identify the amino acid residues responsible for protein–protein binding and led to the identification of a nonapeptide with VP24 binding potential. Subsequently, the ability of this peptide to actually bind VP24 in solution has been assayed using Saturation Transfer Difference NMR and Circular Dichroism. Experimental and molecular modeling data concerning the VP24–peptide complex have been compared and putative peptide binding sites and modes are discussed. [ABSTRACT FROM AUTHOR]

The tree trunk is a microtubule, from which the tubulins are disassembling into the leaves. Keywords: chemical probes; maytansinoids; maytansinol functionalization; microtubules; tubulin EN chemical probes maytansinoids maytansinol functionalization microtubules tubulin 1 1 1 01/27/23 20230124 NES 230124 B Work with the elements of nature b : Our building block, maytansinol, represented as a constellation of stars, is the main protagonist of the story. [Extracted from the article]

The synthesis of the eight stereoisomers of 6-[2-methoxy-3-(piperidinyl)propyl]-5,6-dihydropyran-2-one is reported. The configuration at C2′ and C6 is induced by a sterecontrolled allylation reaction with DIP-Cl. The general structure is the result of merging the structures of two natural products (pironetin and dumetorine) with the aim of discovering a new scaffold for tubulin binders. Docking studies and biological evaluations confirm the validity of the approach. [ABSTRACT FROM AUTHOR]

p-Aminobenzoic acid (pABA) plays important roles in a wide variety of metabolic processes. Herein we report the synthesis, theoretical calculations, crystallographic investigation, and in vitro determination of the biological activity and phytotoxicity of the pABA salt, 2-hydroxyethylammonium p-aminobenzoate (HEA-pABA). The ability of neutral and anionic forms of pABA to interact with TIR1 pocket was investigated by calculation of molecular electrostatic potential maps on the accessible surface area, docking experiments, Molecular Dynamics and Quantum Mechanics/Molecular Mechanics calculations. The docking study of the folate precursor pABA, its anionic form and natural auxin (indole-3-acetic acid, IAA) with the auxin receptor TIR1 revealed a similar binding mode in the active site. The phytotoxic evaluation of HEA-pABA, pABA and 2-hydroxyethylamine (HEA) was performed on the model plant Arabidopsis thaliana ecotype Col 0 at five different concentrations. HEA-pABA and pABA acted as potential auxin-like regulators of root development in Arabidopsis thaliana (0.1 and 0.2 mM) and displayed an agravitropic root response at high concentration (2 mM). This study suggests that HEA-pABA and pABA might be considered as potential new regulators of plant growth. [ABSTRACT FROM AUTHOR]

The performance of an extensive set of density functional theory functionals has been tested against CCSD(T) and MP2 results, extrapolated to the complete basis set (CBS) limit, for the interaction of either DCl or DBr (D = H, HCC, F, and NC) with the aromatic system of benzene. It was found that double hybrid functionals explicitly including dispersion, that is, B2PLYPD and mPW2PLYPD, provide the better agreement with the CCSD(T)/CBS results on both energies and equilibrium geometry, indicating the importance of dispersive contributions in determining this interaction. Among the less expensive functionals, the better performance is provided by the ωB97X and M062X functionals, while the ωB97XD and B97D functionals are shown to work very well for bromine complexes but not so well for chlorine complexes. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The introduction of a hydrophobic group at position 7 of 9-fluorenone-2-carboxylic acid generates new tubulin binders, the design of which is suggested by modeling studies. The synthesis is based on the use of 2,7-dibromo-fluorenone as starting material. The antiproliferative activity on two different cell lines, fluorescent microscopy, flow cytometry, and sedimentation assay tests confirmed the supposed mechanism. [ABSTRACT FROM AUTHOR]

Halogen bond is an important non-covalent interaction which is receiving a growing attention in the study of protein–ligand complexes. Many drugs are halogenated molecules and it has been recently shown that many halogenated ligands establish halogen bonds with biomolecules. As the halogen bond nature is due to an anisotropy of the electrostatic potential around halogen atoms, it is not possible to use traditional force fields based on a set of atom-centred charges to study halogen bonds in biomolecules. We show that the introduction of pseudo-atoms on halogens permits us to correctly describe the anisotropy of the electrostatic potential and to perform molecular dynamics simulations on complexes of proteins with halogenated ligands that reproduce experimental values. The results are compared with crystallographic data and with hybrid quantum mechanics/molecular mechanics calculations. [ABSTRACT FROM AUTHOR]

Tubulin is a heterodimeric protein whose self assembly leads to the formation of protofilaments and of more complex structures called microtubules, key components of the cytoskeleton which have a fundamental role in the cell division process. Due to its biological function, tubulin is the target of many antitumoral molecules that exert their action on proliferating tumoral cells. Among these drugs, vinblastine has been widely used in therapy for a long time, albeit its mechanism of interaction with tubulin has remained elusive until recently. Vinblastine acts as a microtubule destabilizing agent and induces the formation of curved or ring-shaped tubulin polymers instead of linear protofilaments in vitro. In this paper we compare, using molecular dynamics simulations and free energy calculations, the network of interactions that allow the assembly of model linear protofilaments with those present in curved tubulin polymers complexed with vinblastine. It is shown that vinblastine, wedging between tubulin heterodimers, actually mediates part of the interactions between them and acts by crosslinking the two proteins, leading to the observed curved polymers rather than to their disassembly. [ABSTRACT FROM AUTHOR]

Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein–protein interface allows us to identify the amino acids responsible for tubulin–tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells. [ABSTRACT FROM AUTHOR]

Maytansinol, maytansine binding site, tubulin, microtubules, tubulin binders Keywords: maytansinol; maytansine binding site; tubulin; microtubules; tubulin binders EN maytansinol maytansine binding site tubulin microtubules tubulin binders 1 1 1 01/18/22 20220110 NES 220110 B The interdisciplinary character b of the Horizon2020-MSCA-EJD TubInTrain project allowed a challenging study of the peculiarity of maytansinoids as tubulin binders. [Extracted from the article]

The concept of orthogonality between halogen and hydrogen bonding, brought out by Ho and coworkers some years ago, has become a widely accepted idea within the chemists' community. While the original work was based on a common carbonyl oxygen as acceptor for both interactions, we explore here, by means of M06-2X, M11, ωB97X, and ωB97XD/aug-cc-PVTZ DFT calculations, the interdependence of halogen and hydrogen bonding with a shared π-electron system of benzene. The donor groups (specifically NCBr and H2O) were placed on either or the same side of the ring, according to a double T-shaped or a perpendicular geometry, respectively. The results demonstrate that the two interactions with benzene are not strictly independent on each other, therefore outlining that the orthogonality between halogen and hydrogen bonding, intended as energetical independence between the two interactions, should be carefully evaluated according to the specific acceptor group. [ABSTRACT FROM AUTHOR]

Orbitals that are extremely localized on molecular fragments represent a powerful tool for a number of purposes: to cite a few examples, they allow to reduce strongly the complexity of calculations on large systems and are easily transferable from one molecule to another, providing a suitable and efficient way to build up the electronic structure of large molecules. Recently, we have developed efficient algorithms to determine extremely localized molecular orbitals (ELMOs), which will be reviewed in this paper. As a rigorous localization is strictly connected to a reduction in the number of variational parameters, which reflects into an increased value of the associated energy with respect to the Hartree Fock value, we have developed a number of strategies to relax the wavefunction built up using transferred localized orbitals. The extreme localization has also been exploited in connection with the “Divide and Conquer” technique to determine the electron densities of large polypeptides assembled from orbitals computed on small model molecules. Moreover, we will discuss the recent application of the ELMOs in the framework of the hybrid QM/MM methods to describe the frontier region. We will also show that the ELMOs can be used to extract chemical interpretations from numerical results. A variety of applications will be presented. [ABSTRACT FROM AUTHOR]

A theoretical investigation on the nature of the halogen bond through a valence‐bond approach has been carried out with two main goals: (a) finding further confirmations of already existing explanations on the physical origins of the halogen bond and (b) possibly enriching the current models with new details. To achieve these goals we have exploited the spin‐coupled method and we have performed computations on RBr⋯NH3 dimers characterized by a different electron withdrawing power of substituent R to the bromine atom. The analysis of typical spin‐coupled descriptors (eg, shapes and overlaps of the spin‐coupled orbitals, weights of the spin‐coupled structures) in the different cases and in function of the distance between the monomers allowed us to draw qualitative conclusions about the formation and the strength of the halogen bonds. In particular, the investigation not only confirmed the validity of already existing models (ie, σ‐hole and lump‐hole models) but also highlighted interesting new features, such as the fact that the depletion of electron density around the bromine atom does not extend only toward the acceptor of the halogen bond, but also in the opposite direction (toward the substituent of the halogen), thus forming a sort of σ‐tunnel, rather than a simple σ‐hole. [ABSTRACT FROM AUTHOR]

Highlights from the article: Front Cover: Stereodivergent Diversity-Oriented Synthesis: Exploiting the Versatility of 2-Piperidine Ethanol (Eur. J. Org. Chem. 25/2019) B The Front Cover b shows a playful representation of the fascination to explore, that always moved science forward. The 2-piperidine ethanol appears as a kite in the hands of a bold researcher to give vent to the imagination, looking for new structures and landing on known chemical entities.