Intermolecular Contacts Research Articles

Synthesis, structural characterization of supramolecular cocrystals of bis(3-hydroxy-1-methylpyridin-1-ium iodide)-18-crown-6

Abstract A new supramolecular cocrystal of bis(3-hydroxy-1-methylpyridin-1-ium iodide)-18-crown-6 (I) has been synthesized successfully from 3-hydroxypyridine, methyl iodide and 18-crown-6 (18C6). The cocrystal was characterized by FT-IR, UV-DRS and PL spectroscopy, single crystal and powder X-ray diffraction (XRD) analysis, SEM and EDS analysis, and thermogravimetric analysis. The bulk phase purity of the compound is confirmed by powder XRD analysis, whereas single-crystal XRD confirms that it packs in a monoclinic system with centrosymmetric space group (P21/c). Single crystal XRD shows that the asymmetric unit is C6H12O3, [C6H8NO]+[I]¯. The presence of C–H⋯O, C–H⋯I and O–H⋯I intermolecular contacts helps to achieve crystal cohesion. The direct band gap energy has been estimated to be 3.21 eV using diffuse reflectance spectral measurements. Thermogravimetric analysis was employed to determine the compound’s thermal behaviour concerning temperature. EDS and SEM investigations were used to examine the elemental composition and surface morphology of the compound.

Unraveling the structural features of a contemporary 1,4-dihydropyridine derivative through crystallographic and computational study

Crystal structure of a 1,4 dihydropyridine derivative with IUPAC name, 4-(4‑hydroxy-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid bis-[(2-choloro-phyenyl)-amide] has been solved and the final refinement value converged to 0.0898 with a water molecule present in the lattice. Hirshfeld surfaces analysis shows the estimate of major relative contributions to various intermolecular contacts. The dnorm surface, shape index, curvedness and hydrogen bonding in the molecule are also reported to visualize the crystal shape, curvature and neighbor interactions. The DFT calculations were carried to address the role of the water molecule in the solved crystal structure and how the water molecule plays as a linker to hold the molecules together through hydrogen bonds with the functional groups.

Structural determinants of odorant-binding proteins affecting their ability to form amyloid fibrils

The formation of amyloid fibrils is associated with many severe pathologies as well as the execution of essential physiological functions by proteins. Despite the diversity, all amyloids share a similar morphology and consist of stacked β-strands, suggesting high amyloidogenicity of native proteins enriched with β-structure. Such proteins include those with a β-barrel-like structure with β-strands arranged into a cylindrical β-sheet. However, the mechanisms responsible for destabilization of the native state and triggering fibrillogenesis have not thoroughly explored yet. Here we analyze the structural determinants of fibrillogenesis in proteins with β-barrel structures on the example of odorant-binding protein (OBP), whose amyloidogenicity was recently demonstrated in vitro. We reveal a crucial role in the fibrillogenesis of OBPs for the “open” conformation of the molecule. This conformation is achieved by disrupting the interaction between the β-barrel and the C-terminus of protein monomers or dimers, which exposes “sticky” amyloidogenic sites for interaction. The data suggest that the “open” conformation of OBPs can be induced by destabilizing the native β-barrel structure through the disruption of: 1) intramolecular disulfide cross-linking and non-covalent contacts between the C-terminal fragment and β-barrel in the protein's monomeric form, or 2) intermolecular contacts involved in domain swapping in the protein's dimeric form.

Crystal-Structure Control of Molecular Semiconductors by Methylthiolation: Toward Ultrahigh Mobility.

ConspectusThe crystal structure of organic semiconductors has been regarded as one of the crucial factors for realizing high-performance electronic devices, such as organic field-effect transistors. However, although the control of crystal structures of organic semiconductors has been examined in the last two decades of intensive efforts of the development of organic semiconductors, active measures to control crystal structures enabling high carrier mobility are still limited. In 2016, our research group noticed that regioselective methylthiolation could provide a selective crystal structure change from an ordinary herringbone structure to a pitched π-stacking structure, similar to the crystal structure of rubrene, in the benzo[1,2-b:4,5-b']dithiophene (BDT) system. Following this serendipitous finding, our group systematically investigated the relationship between the molecular and crystal structures of a range of methylthiolated aromatic and heteroaromatic compounds.This Account provides a comprehensive overview of our research efforts and advancements in the development of methylthiolated small-molecule-based organic semiconductors (molecular semiconductors). We first describe the outline of the past development of molecular semiconductors, focusing on the types of crystal structures of high-performance molecular semiconductors. Then, we describe our findings on the drastic crystal structure change in the BDT system upon methylthiolation, detailing the causes of the change in terms of the intermolecular contacts and intermolecular interaction energies. This is followed by the confirmation of the generality of the crystal-structure change by methylthiolation of a series of acene and heteroacenes, where the herringbone structure in the parent system is unexceptionally transformed into the pitched π-stacking structure, a promising crystal structure for high-mobility molecular semiconductors well exemplified by the prototypical molecular semiconductor, rubrene. In fact, the methylthiolated anthradithiophene afforded comparable high mobility to rubrene in single-crystal field-effect transistors. Then, we demonstrate that the sandwich herringbone structures of peri-condensed polycyclic aromatic hydrocarbons, including pyrene, perylene, and peropyrene, change into brickwork crystal structures upon methylthiolation and that, among these compounds, very promising molecular semiconductors, methylthiolated pyrene and peropyrene, showing ultrahigh mobility of 30 cm2 V s-1, are realized.Through the studies, by gaining insights into the underlying mechanisms driving the crystal structure changes, we lay a strong foundation for tackling challenges related to controlling the crystal structures and developing high-performance molecular semiconductors. This will be a distinct approach from the past activities in the development of molecular semiconductors that mainly focused on molecules themselves, including their synthesis, properties, and characterization. We thus anticipate that our findings and the present Account will open the door to a new era of the development of molecular semiconductors.

Synthesis and characterization of bis[(dimethylphosphanylethynyl)dimethylsilyl]methane-digold(I) dichloride

Abstract The reaction of chlorodimethylphosphane with dilithiated bis(ethynyldimethylsilyl)methane leads to the corresponding bis[(dimethylphosphanylethynyl)dimethylsilyl]methane (1) which reacts readily with chloroauric acid in the presence of a reductant to form its dinuclear chlorogold(I) complex (2). The terminal chloride units of this compound can be substituted by reaction with nucleophiles. Furthermore, the metallophilic host functionality of the dinuclear complex 2 towards metallophilic atoms such as copper, silver, and thallium was tested. The crystal structure of bis[(dimethylphosphanylethynyl)dimethylsilyl]methane-digold(I) dichloride (2) is presented, which shows chains of the molecules aggregated by intermolecular aurophilic contacts.

Experimental and theoretical studies of methyl 1-(2-chloroacetyl)-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate: Insights from synthesis, spectroscopic, crystal structure, Hirshfeld surface, DFT, ELF, RDG, IRI, ADMET and docking studies

Methyl 1-(2-chloroacetyl)-4‑hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (compound 2) was synthesized by the condensation of 3-carboxymethyl-2,6-diphenylpiperidine-4-one with chloroacetylchloride, and characterized by FT-IR spectroscopy. Further confirmation of the molecular structure was obtained by the single crystal X-ray diffraction (SC-XRD) technique. The study revealed that the piperidine ring adopts boat conformation with equatorial orientation of two phenyl rings at C-2 and C-6. Intermolecular contacts and hydrogen bonding interactions were explored by Hirshfeld surface and 2D fingerprint analyses, showing that the major contact were H∙∙∙H (57.7 %), C∙∙∙H/H∙∙∙C (14.2 %), O∙∙∙H/H∙∙∙O (15.3), Cl∙∙∙H/H∙∙∙Cl (7.1 %) and C∙∙∙Cl/Cl∙∙∙C (12.7 %). Intramolecular interaction was examined through the Radiant density gradient (RDG), Interaction region indicator (IRI), Electron localization function (ELF), and localized orbital locator (LOL) to understand hyperconjugration and π-electrons delocalization in the molecule. DFT studies such as structure optimization, HOMO-LUMO orbital analysis and molecular electrostatic potential were conducted for the title compound. The topology of the molecular arrangement and intermolecular interaction energies were determined through 3D energy framework analysis. Subsequently, the compound 2 was subjected to ADMET analysis to extend its scope of bioavailability. Molecular docking studies were then employed using the tyrosine kinase inhibitor, epidermal growth factor receptor (EGFR) enzymes (PDB ID: 4WKQ and 6JOL). The study revealed significant interactions between the title ligand structure and active sites of selected proteins complex.

The NMR structure of the Orf63 lytic developmental protein from lambda bacteriophage

The orf63 gene resides in a region of the lambda bacteriophage genome between the exo and xis genes and is among the earliest genes transcribed during infection. In lambda phage and Shiga toxin (Stx) producing phages found in enterohemorrhagic Escherichia coli (EHEC) associated with food poisoning, Orf63 expression reduces the host survival and hastens the period between infection and lysis thereby giving it pro-lytic qualities. The NMR structure of dimeric Orf63 reveals a fold consisting of two helices and one strand that all make extensive intermolecular contacts. Structure-based data mining failed to identify any Orf63 homolog beyond the family of temperate bacteriophages. A machine learning approach was used to design an amphipathic helical ligand that bound a hydrophobic cleft on Orf63 with micromolar affinity. This approach may open a new path towards designing therapeutics that antagonize the contributions of Stx phages in EHEC outbreaks.

Structure‐Based Approaches for the Prediction of Alzheimer's Disease Inhibitors: Comparative Interactions Analysis, Pharmacophore Modeling and Molecular Dynamics Simulations

AbstractDue to its significant role in neurodegeneration, Cyclin‐dependent kinase 5 (CDK5) has emerged as a potential target for addressing neuropathological disorders, including Alzheimer's disease (AD). The application of CDK5 inhibitors has demonstrated promise in the treatment of AD. This prompted us to model this interesting target using a computational workflow named Docking‐based Comparative Intermolecular Contacts Analysis (dbCICA). Approaches including 3D‐QSAR, genetic algorithm, and pharmacophore modeling were employed to discover new CDK inhibitors.

Folding-upon-binding pathways of an intrinsically disordered protein from a deep Markov state model

A central challenge in the study of intrinsically disordered proteins is the characterization of the mechanisms by which they bind their physiological interaction partners. Here, we utilize a deep learning-based Markov state modeling approach to characterize the folding-upon-binding pathways observed in a long timescale molecular dynamics simulation of a disordered region of the measles virus nucleoprotein NTAIL reversibly binding the X domain of the measles virus phosphoprotein complex. We find that folding-upon-binding predominantly occurs via two distinct encounter complexes that are differentiated by the binding orientation, helical content, and conformational heterogeneity of NTAIL. We observe that folding-upon-binding predominantly proceeds through a multi-step induced fit mechanism with several intermediates and do not find evidence for the existence of canonical conformational selection pathways. We observe four kinetically separated native-like bound states that interconvert on timescales of eighty to five hundred nanoseconds. These bound states share a core set of native intermolecular contacts and stable NTAIL helices and are differentiated by a sequential formation of native and non-native contacts and additional helical turns. Our analyses provide an atomic resolution structural description of intermediate states in a folding-upon-binding pathway and elucidate the nature of the kinetic barriers between metastable states in a dynamic and heterogenous, or "fuzzy", protein complex.

2,5-diphenyloxazole and 4-pyrrolidinopyridine as conformers to picric acid: Structural characterization coupled with Multivariate Statistical Analysis

In this study, 4-pyrrolidinopyridine (PPY) and 2,5-diphenyloxazole (DPO) were employed as N-heterocyclic derivatives to synthesize novel picrate salts. These salts were subsequently subjected to characterization using infrared spectroscopy, ultraviolet spectroscopy, and single-crystal X-ray diffraction. Comparison of these structures with entries in the Cambridge Structural Database (CSD) and the application of two multivariate statistical analyses, namely Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA), facilitated the differentiation of salts and co-crystals based on the structural behaviors of the picrate molecule. Additionally, Hirshfield Surface Analysis and 2D fingerprint plots were employed to investigate intermolecular contacts. The fluorescence emission spectra revealed that compound 2 has the potential to serve as a probe for turn-off detection of picric acid (PA).

A novel pyrazole derivative as COVID-19 main protease inhibitor: Synthesis, quantum computational studies, pharmacokinetic properties, drug likeness, molecular docking and dynamics simulation; a CADD approach

2-(3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-4H benzo[d][1,3]oxazin-4-one (2-BCBO) compound, was synthesized by the reaction of 3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid in acetonitrile and methane sulfonyl chloride. The monoclinic crystal structure in C2/c space group of the compound was unveiled through single-crystal X-ray diffraction studies. A prediction model was employed to investigate the influence of intermolecular contacts on molecular packing in the crystalline phase. The model incorporated both Hirshfeld surface and 2D fingerprint models to gain a comprehensive understanding of the strength of these contacts. The calculation of the total interaction energy was conducted by utilizing the three-dimensional molecular energy frameworks and further, employed density functional theory to examine molecular orbital characteristics and key factors associated with chemical reactivity. The application of topological analysis techniques, such as QTAIM and NCI, provided further insight regarding the attraction and repulsive interactions shown by the molecule. The pharmacokinetic properties of the 2-BCBO molecule have also been examined using ADMET analysis, which is important in drug discovery and development. In addition, the molecular docking study to determine the inhibitory effect of the investigated ligand on the main protease of new coronavirus (COVID-19), followed by molecular dynamics simulations, and it is found that both the results are in good agreement. The 2-BCBO could be accepted as a lead molecule to treat the coronavirus.

Speeding-up the Determination of Protein-Ligand Affinities by STD NMR: The Reduced Data Set STD NMR Approach (rd-STD NMR).

STD NMR spectroscopy is a powerful ligand-observed NMR tool for screening and characterizing the interactions of small molecules and low molecular weight fragments with a given macromolecule, identifying the main intermolecular contacts in the bound state. It is also a powerful analytical technique for the accurate determination of protein-ligand dissociation constants (KD) of medium-to-weak affinity, of interest in the pharmaceutical industry. However, accurate KD determination and epitope mapping requires a long series of experiments at increasing saturation times to carry out a full analysis using the so-called STD NMR build-up curve approach and apply the "initial slopes approximation". Here, we have developed a new protocol to bypass this important limitation, which allows us to obtain initial slopes by using just two saturation times and, hence, to very quickly determine precise protein-ligand dissociation constants by STD NMR.

Structural and spectroscopic study and intermolecular chalcogen bonding interactions in 1,3-dicarbonyl compounds

Intra- and intermolecular contacts in 1,3-dicarbonyl compounds are dominated by O–H⋯O bonds. When molecules face each other, the unusual intermolecular O⋯O bonds can reinforce adjacent O–H⋯O bonds and form centrosymmetric dimers.

Silver nanoparticles alter the dimerization of Aβ42 studied by REMD simulations.

The aggregation of amyloid beta (Aβ) peptides is associated with the development of Alzheimer's disease (AD). However, there has been a growing belief that the oligomerization of Aβ species in different environments has a neurotoxic effect on the patient's brain, causing damage. It is necessary to comprehend the compositions of Aβ oligomers in order to develop medications that may effectively inhibit these neurotoxic forms that affect the nervous system of AD patients. Thus, dissociation or inhibition of Aβ aggregation may be able to prevent AD. To date, the search for traditional agents and biomolecules has largely been unsuccessful. In this context, nanoparticles have emerged as potential candidates to directly inhibit the formation of Aβ oligomers. The oligomerization of the dimeric Aβ peptides with or without the influence of a silver nanoparticle was thus investigated using temperature replica-exchange molecular dynamics (REMD) simulations. The physical insights into the dimeric Aβ oligomerization were clarified by analyzing intermolecular contact maps, the free energy landscape of the dimeric oligomer, secondary structure terms, etc. The difference in obtained metrics between Aβ with or without a silver nanoparticle provides a picture of the influence of silver nanoparticles on the oligomerization process. The underlying mechanisms that are involved in altering Aβ oligomerization will be discussed. The obtained results may play an important role in searching for Aβ inhibitor pathways.

Исследование кристаллических структур 7-иод-8-оксихинолин-5-сульфонатов алкилтрифенилфосфония [Ph3PAlk][OSO2C9NH4(I-7)(OH-8)], Alk = CH2Ph, CH=CHMe, CH2C≡CH

From alkyltriphenylphosphonium bromides and 7-iodo-8-hydroxyquinoline-5-sulfonic acid in water, ionic alkyltriphenylphosphonium 7-iodo-8-hydroxyquinoline-5-sulfonates Ph3PAlk][OSO2C9NH4(I-7)(OH-8)], Alk = CH2Ph (1), CH=CHMe (2), CH2C≡CH (3) have been obtained. Crystals 1 [C34H27NO4PSI, M 703.50; monoclinic system, symmetry group P21/c; cell parameters: a = 8.805(4), b = 16.146(10), c = 20.833(11) Å; β = 93.410(17), V = 2956(3) Å3, Z = 4; rcalc = 1.581 g/cm3], 2 [C30H25NO4PSI, M 653.44; rhombic system, symmetry group P212121; cell parameters: a = 9.382(3), b = 14.033(4), c = 21.035(6) Å; a = β = g = 90.00 deg., V = 2769.5(15) Å3, Z = 4; rcalc = 1.567 g/cm3], 3 [C30H27NO6PSI, M 687.46; monoclinic system, symmetry group P21/n; cell parameters: a = 9.426(3), b = 19.239(5), c = 16.088(5) Å; β = 97.296(14) deg., V = 2894.0(15) Å3, Z = 4; rcalc = 1.578 g/cm3]. According to the X-ray diffraction data, the phosphorus atoms in cations 1–3 have a distorted tetrahedral coordination, while the sulfonate anions have a regular geometry with a tetrahedral sulfur atom. The P–C bond lengths vary in the range 1.772(3)−1.815(2) Å; the CPC bond angles take values of 106.08(11)°−112.33(11)°. In the arenesulfonate anions of the complexes, the S–C distances are close to each other [1.781(2)–1.7920(19) Å], the S–O bonds are practically aligned [1.4464(16)–1.4590(17) Å]. In the crystal of hydrate 3 [Ph3PCH2C≡CH][OSO2C9NH4(I-7)(OH-8)] ∙ 2H2O, water molecules participate in formation of a dimeric anion (the O∙∙∙H and N∙∙∙H distances are 1.93 and 2.03 Å, while the arene rings of the sulfonate ligands are almost parallel (the angle between them is 3.24°)). Other water molecules link the dimeric anions into a chain with hydrogen bonds (the O∙∙∙H distances equal 2.12 and 2.15 Å). The structural organization in complexes 1–3 is mainly due to weak intermolecular contacts of the O···H type: 2.04–2.69 Å (1), 2.05–2.69 Å (2), 2.12–2.15 Å (3).

Influence of N-protonation on electronic properties of acridine derivatives by quantum crystallography.

Applications of 9-aminoacridine (9aa) and its derivatives span fields such as chemistry, biology, and medicine, including anticancer and antimicrobial activities. Protonation of such molecules can alter their bioavailability as weakly basic drugs like aminoacridines exhibit reduced solubility at high pH levels potentially limiting their effectiveness in patients with elevated gastric pH. In this study, we analyse the influence of protonation on the electronic characteristics of the molecular organic crystals of 9-aminoacridine. The application of quantum crystallography, including aspherical atom refinement, has enriched the depiction of electron density in the studied systems and non-covalent interactions, providing more details than previous studies. Our experimental results, combined with a topological analysis of the electron density and its Laplacian, provided detailed descriptions of how protonation changes the electron density distribution around the amine group and water molecule, concurrently decreasing the electron density at bond critical points of N/O-H bonds. Protonation also alters the molecular architecture of the systems under investigation. This is reflected in different proportions of the N⋯H and O⋯H intermolecular contacts for the neutral and protonated forms. Periodic DFT calculations of the cohesive energies of the crystal lattice, as well as computed interaction energies between molecules in the crystal, confirm that protonation stabilises the crystal structure due to a positive synergy between strong halogen and hydrogen bonds. Our findings highlight the potential of quantum crystallography in predicting crystal structure properties and point to its possible applications in developing new formulations for poorly soluble drugs.

Dioxygen-halogen bonding exemplified by crystalline peroxosolvates of N,N'-bis(haloacetyl) bispidines.

The halogen bonding in molecular crystals and supramolecular assemblies has been widely investigated. Special attention is given to the molecular structures capable of simultaneously exhibiting different types of non-covalent interactions, including conventional hydrogen bonds and halogen bonds. This paper systematically analyzes crystalline peroxosolvates of bispidine-based bis-amide derivatives, containing haloacetic acid residues, namely previously reported 1,1'-(1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-iodooethanone) peroxosolvate C13H20I2N2O2·H2O2 (1) and four new crystalline compounds, 1,1'-(1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-bromoethanone) peroxosolvate C13H20Br2N2O2·H2O2 (2), 1,1'-(9-hydroperoxy-9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-iodoethanone) peroxosolvate C13H20I2N2O5·0.5H2O2 (3), 1,1'-(9-hydroperoxy-9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-bromoethanone) peroxosolvate C13H20Br2N2O5·H2O2 (4), and 1,1'-(9-hydroperoxy-9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-chloroethanone) peroxosolvate C13H20Cl2N2O5·H2O2 (5). Compounds 2-5 were synthesized for the first time and their crystal structures were determined by single-crystal X-ray diffractometry (SCXRD). To the best of our knowledge, 3-5 are unprecedented crystalline hydrogen peroxide adducts of organic hydroperoxides (R-OOH). Short intermolecular contacts between halogen and hydroperoxo oxygen atoms were found in 1-3. The halogen bonding of C-I(Br) fragments with dioxygen species in compounds 1-3 as well as in the previously reported cocrystal of diacetone diperoxide with triodotrinitrobenzene (6) was identified through reduced density gradient analysis, Hirshfeld surface analysis, and Bader analysis of crystalline electron density. The interactions were quantified using the electron density topological properties acquired from the periodic DFT calculations and evaluated to lie in the range of 9-19 kJ mol-1. A distinctive spectral feature was revealed for this type of interaction, involving a red shift of the characteristic O-O stretching vibration by about 6 cm-1, which appeared in IR spectra as a narrow low-intensity band in the region 837-872 cm-1.

Solid-state NMR spectroscopic analysis for structure determination of a zinc-bound catalytic amyloid fibril.

Zinc ions are commonly involved in enzyme catalysis and protein structure stabilization, but their coordination geometry of zinc-protein complex is rarely determined. Here, in this chapter, we introduce a systematic solid-state NMR approach to determine the oligomeric assembly and Zn2+ coordination geometry of a de novo designed amyloid fibrils that catalyze zinc dependent ester hydrolysis. NMR chemical shifts and intermolecular contacts confirm that the peptide forms parallel-in-register β-sheets, with the two forms of Zn2+ bound histidines in each peptide. The amphiphilic parallel β-sheets assemble into stacked bilayers that are stabilized by hydrophobic side chains between β-sheets. The conformations of the histidine side chains, determined by 13C-15N distance measurements, reveal how histidines protrude from the β-sheet. 1H-15N correlation spectra show that the single-Zn2+ coordinated histidine associated with dynamic water. The resulting structure provides insight into how metal ions contribute to stabilizing the protein structure and driving its catalytic reactivity.

Azido-mediated intermolecular interactions of transition metal complexes.

The coordinated azido ligand has a variety of ways to establish intermolecular contacts whose nature is computationally analysed in this work on dimers of the [N3-Hg(CF3)] complex with different interactions involving only N⋯N contacts, or with an additional Hg⋯N contact. The applied tools include the molecular electrostatic map of the monomer, an energy decomposition analysis (EDA), a topological AIM analysis of the electron density and the study of NCI (non-covalent interactions) isosurfaces. The interactions between two azido ligands are found to be weakly stabilizing (by 0.2 to 2.7 kcal mol-1), topology-dependent and require dispersion forces to complement orbital and electrostatic stabilization. Those interactions are supplemented by the formation of simultaneous Hg⋯N secondary interactions by about -1 kcal mol-1, and by the ability of the monomer to simultaneously interact with several neighbours in the crystal structure.

Molecular bowls for inclusion complexation of toxic anticancer drug methotrexate.

We describe the preparation and study of novel cavitands, molecular bowls 16+ and 26+, as good binders of the anticancer drug methotrexate (MTX). Molecular bowls are comprised of a curved tribenzotriquinacene (TBTQ) core conjugated to three macrocyclic pyridinium units at the top. The cavitands are easily accessible via two synthetic steps from hexabromo-tribenzotriquinacene in 25% yield. As amphiphilic molecules, bowls 16+ and 26+ self-associate in water by the nucleation-to-aggregation pathway (NMR). The bowls are preorganized, having a semi-rigid framework comprising a fixed bottom with a wobbling pyridinium rim (VT NMR and MD). Further studies, both experimental (NMR) and computational (DFT and MCMM), suggested that a folded MTX occupies the cavity of bowls wherein it forms π-π, C-H-π, and ion pairing intermolecular contacts but also undergoes desolvation to give stable binary complexes (μM) in water. Moreover, a computational protocol is introduced to identify docking pose(s) of MTX inside molecular bowls from NMR shielding data. Both molecular bowls have shown in vitro biocompatibility with liver and kidney cell lines (MTS assay). As bowl 26+ is the strongest binder of MTX reported to date, we envision it as an excellent candidate for further studies on the way toward developing an antidote capable of removing MTX from overdosed cancer patients.