Low Valence Triel (I) Systems as Hydrogen Bond Acceptors and their Stability with Respect to Triel (III) Compounds.

A theoretical study of the complexes formed by carbene like Al(I), Ga(I), In(I) and Tl(I) compounds with hydrogen bond donors (HBD), XH (HCCH, HSH,HOH, HCN, HCl, HBr, HF, and HNC) have been carried out at MP2 computational level. The isolated triel(I) compounds show a negative region of the molecular electrostatic potential region associated with the triel atom suitable to interact with electron deficient groups. This region is associated to a lone pair based on the ELF analysis and to the location of the HOMO orbital. The complexes are similar to those found in nitrogen heterocyclic carbenes (NHC) with HBD. In addition, the oxidative addition reactions of those complexes to yield the corresponding valence III compounds have been characterized. The Al(III) compounds are much more stable than the corresponding Al(I) complexes. However, the stability of the triel(III) compounds decreases with the size of the triel atom and for the thallium derivatives, the Tl(I) complexes are more stable than the Tl(III) compounds in accordance with the number of the structures found in the CSD. The barrier of the TS connecting the triel(I) and triel(III) systems increases with the size of the triel atoms.

Reduction of Substituted Benzo-Fused Cyclic Sulfonamides with Mg-MeOH: An Experimental and Computational Study.

A study involving the use of Mg-MeOH for the double reductive cleavage of both N-S and C-S bonds in a series of 11 benzo-fused cyclic sulfonamides is reported. Examples where the sulfonamide nitrogen atom is part of a pyrrolidine ring effectively undergo reduction, as long as a methoxy substituent is not para-positioned in the aromatic ring, relative to the sulfonyl group. In contrast, if the nitrogen atom is contained within an aromatic ring (pyrrole or indole), the presence of a para-methoxy substituent does not prohibit reduction. If deuterated methanol is used, aromatic ortho-deuterium incorporation was observed. To better understand how structure affects reactivity, density functional theory calculations were performed using three functionals. Results using CAM-B3LYP were found to best correlate with experimental observations, and these demonstrate the impact that the different aromatic substitution patterns and types of N-atom have on the lowest unoccupied molecular orbital (LUMO) energies and adiabatic electron affinities.

Evaluation of Electron Density Shifts in Noncovalent Interactions.

In the present paper, we report the quantitative evaluation of the electron density shift (EDS) maps within different complexes. Values associated with the total EDS maps exhibited good correlation with different quantities such as interaction energies, Eint, intermolecular distances, bond critical points, and LMOEDA energy decomposition terms. Besides, EDS maps at different cutoffs were also evaluated and related with the interaction energies values. Finally, EDS maps and their corresponding values are found to correlate with Eint within systems with cooperative effects. To our knowledge, this is the first time that the EDS has been quanitatively evaluated.

Rivalry between Regium and Hydrogen Bonds Established within Diatomic Coinage Molecules and Lewis Acids/Bases.

A theoretical study of the complexes formed by Ag2 and Cu2 with different molecules, XH (FH, ClH, OH2 , SH2 , HCN, HNC, HCCH, NH3 and PH3 ) that can act as hydrogen-bond donors (Lewis acids) or regium-bond acceptors (Lewis bases) was carried out at the CCSD(T)/CBS computational level. The heteronuclear diatomic coinage molecules (AuAg, AuCu, and AgCu) have also been considered. With the exception of some of the hydrogen-bonded complexes with FH, the regium-bonded binary complexes are more stable. The AuAg and AuCu molecules show large dipole moments that weaken the regium bond (RB) with Au and favour those through the Ag and Cu atoms, respectively.

In-vitro and in-vivo investigations into the carbene-gold anticancer drug candidates NHC*-Au-SCSNMe2 and NHC*-Au-S-GLUC against advanced prostate cancer PC3.

The anticancer drug candidates 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative exhibited nanomolar in-vitro activity against prostate cancer cells advanced prostate cancer (PC3) and micromolar inhibition of mammalian thioredoxin reductase. Encouraging maximum tolerable dose experiments led to human prostate cancer subcutaneous xenograft experiments; 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative were applied twelve times at two doses in groups of n = 5 PC3 to tumor-bearing NMRI:nu/nu mice. 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative at the dose of 10 and 20 mg/kg showed good tolerability, while no significant body weight loss was seen in both groups. In particular, for the drug 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) dimethylamino dithiocarbamate the tumor growth inhibition suggested to be dose dependent, reflected by the respective optimal T/C values of 0.45 at the dose of 10 mg/kg and of 0.31 at the dose of 20 mg/kg. By contrast, the 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate derivative treated groups showed no indication for dose-dependent antitumoral activity, as reflected by the optimal T/C values of 0.44 for the 10 mg/kg and for the 20 mg/kg treated mice. Immunohistochemical experiments involving Ki67 staining of tumor tissue showed that both compounds reduced PC3 cell proliferation against the difficult to treat advanced human prostate tumors derived from PC3.

Interaction between Trinuclear Regium Complexes of Pyrazolate and Anions, a Computational Study.

The geometry, energy and electron density properties of the 1:1, 1:2 and 1:3 complexes between cyclic (Py-M)3 (M = Au, Ag and Cu) and halide ions (F-, Cl- and Br-) were studied using Møller Plesset (MP2) computational methods. Three different configurations were explored. In two of them, the anions interact with the metal atoms in planar and apical dispositions, while in the last configuration, the anions interact with the CH(4) group of the pyrazole. The energetic results for the 1:2 and 1:3 complexes are a combination of the specific strength of the interaction plus a repulsive component due to the charge:charge coulombic term. However, stable minima structures with dissociation barriers for the anions indicate that those complexes are stable and (Py-M)3 can hold up to three anions simultaneously. A search in the CSD confirmed the presence of (Pyrazole-Cu)3 systems with two anions interacting in apical disposition.

Anion Recognition by Neutral and Cationic Iodotriazole Halogen Bonding Scaffolds.

A computational study of the iodide discrimination by different neutral and cationic iodotriazole halogen bonding hosts was carried out by means of Density Functional Theory. The importance of the size of the scaffold was highlighted and its impact observed in the binding energies and intermolecular X···I distances. Larger scaffolds were found to reduce the electronic repulsion and increase the overlap between the halide electron lone pair and the corresponding I-C antibonding orbital, increasing the halogen bonding interactions. Additionally, the planarity plays an important role within the interaction, and can be tuned using hydroxyl to perform intramolecular hydrogen bonds (IMHB) between the scaffold and the halogen atoms. Structures with IMHB exhibit stronger halogen bond interactions, as evidenced by the shorter intramolecular distances, larger electron density values at the bond critical point and more negative binding energies.

Theoretical Investigation of Cyano-Chalcogen Dimers and Their Importance in Molecular Recognition.

In this manuscript the different noncovalent interactions established between (HYCN)2 dimers (Y=S, Se and Te) have been studied at the MP2 and CCSD(T) level of theory. Several homodimers have been taken into account, highlighting the capacity of these compounds to act both as electron donor and acceptor. The main properties studied were geometries, binding energy (Eb ), and molecular electrostatic potential (MEP). Given the wide application of chalcogen bonds, and more specifically of cyano-chalcogen moieties in molecular recognition, natural bond orbital (NBO), "atoms-in-molecules" (AIM), and electron density shift (EDS) analysis were also used to analyse the different noncovalent interactions upon complexation. The presence of hydrogen, chalcogen and dipole-dipole interactions was confirmed and their implications on molecular recognition were analysed.

Sequestration of CO2 by Phosphatrane Molecules.

The stationary points for the reaction between the CO2 and nine different phosphatranes molecules have been characterized by means of MP2 computational methods. Two minima structures have been located: a pnicogen bonded complex where one of the oxygen atoms of CO2 acts as electron donor and an adduct that presents a covalent P-C linkage. The corresponding transition state structure linking the two minima has also been characterized. In gas phase, the pnicogen bonded complex is more stable than the corresponding adduct except in one case. In contrast, the inclusion of the solvent effect (toluene and THF), reverts the stability, being in all cases the different adducts more stable than the pnicogen bonded complexes. The electronic properties of the systems have been analysed with the Quantum Theory of Atoms in Molecules (QTAIM) and Electron Density Shift (EDS) methods.

Understanding Regium Bonds and their Competition with Hydrogen Bonds in Au2 :HX Complexes.

A theoretical study of the regium and hydrogen bonds (RB and HB, respectively) in Au2 :HX complexes has been carried out by means of CCSD(T) calculations. The theoretical study shows as overall outcome that in all cases the complexes exhibiting RB are more stable that those with HB. The binding energies for RB complexes range between -24 and -180 kJ ⋅ mol-1, whereas those of the HB complexes are between -6 and -19 kJ ⋅ mol-1 . DFT-SAPT also indicated that HB complexes are governed by electrostatics, but RB complexes present larger contribution of the induction term to the total attractive forces. 197 Au chemical shifts have been calculated using the relativistic ZORA Hamiltonian.

Cyclohexane-Based Scaffold Molecules Acting as Anion Transport, Anionophores, via Noncovalent Interactions.

A theoretical study of a variety of cyclohexane-based anion transporters interacting with the chloride anion has been conducted using density functional theory. The calculations have been performed in the gas phase but also, in order to describe the solvation effects on the interaction, two different solvents-chloroform and dimethylsulfoxide-have been taken into account. Gas-phase interaction energies within the complexes are found to be up to 400 kJ/mol, while, when solvent effects are considered, the interaction energy values decreased drastically concomitantly with an elongation in the interatomic distances. Atoms in molecules and natural bond analysis corroborate the trends found for the intermolecular energies and Cl···H distances, suggesting strong donations from the Cl- anion into the σ*H-N antibonding orbitals, as well as with noncovalent interaction plots showing large areas of electron density overlap within the chloride anion surroundings.

Planarity or Nonplanarity: Modulating Guanidine Derivatives as α2-Adrenoceptors Ligands.

A theoretical study has been carried out at the M062X/6-311++G(d,p) computational level to search for a rationale on ligands' affinity toward α2-adrenoceptors by estimating the nature and strength of intramolecular hydrogen bonds potentially formed (by means of the QTAIM and NBO approaches) as well as the degree of deviation from planarity that could be observed in some of the compounds. Four different families have been studied: thiophen-2-yl, 3-carboxylatethiophen-2-yl esters, 3-cyanothiophen-2-yl, and 2-thiazolyl guanidinium derivatives. In the case of the thiophen-2-yl guanidines not substituted in the 3 position, nonplanarity was always observed, whereas in the thiazole series, intramolecular hydrogen bonds were identified between the guanidinium and the thiazole ring forcing the systems to planarity. Regarding the carboxylic esters, two different rotamers were found: quasi-planar and quasi-perpendicular systems with very similar energy. Both of these isomers can form different nets of intramolecular hydrogen bonds and other types of noncovalent interactions. Different physicochemical properties such as basicity, solubility, or lipophilicity were calculated for these systems, but no correlation to the degree of planarity was found. However, when comparing the α2-ARs affinity with the planarity of the molecules, a trend appears in the thiophen-2-yl guanidinium series indicating that lack of planarity seems to be optimal for α2-ARs engagement.

Modulating intramolecular chalcogen bonds in aromatic (thio)(seleno)phene-based derivatives.

Intramolecular interactions have been proven to be the key to conformational control in drug-design. While chalcogen interactions have been shown to be present in certain ligands of the GK-GKRP target protein, in the present study, intramolecular chalcogen interactions through selenium are found to be even more promising since they form stronger interactions. Also, the flexibility/rigidity of the carbon backbone of the corresponding ligands is crucial in the conformational stability.

Cooperative Effects in Weak Interactions: Enhancement of Tetrel Bonds by Intramolecular Hydrogen Bonds.

A series of silyl and germanium complexes containing halogen atoms (fluorine and chlorine atoms) and exhibiting tetrel bonds with Lewis bases were analyzed by means of Møller-Plesset computational theory. Binding energies of germanium derivatives were more negative than silicon ones. Amongst the different Lewis bases utilized, ammonia produced the strongest tetrel bonded complexes in both Ge and Si cases, and substitution of the F atom by Cl led to stronger complexes with an ethylene backbone. However, with phenyl backbones, the fluorosilyl complexes were shown to be less stable than the chlorosilyl ones, but the opposite occurred for halogermanium complexes. In all the cases studied, the presence of a hydroxyl group enhanced the tetrel bond. That effect becomes more remarkable when an intramolecular hydrogen bond between the halogen and the hydrogen atom of the hydroxyl group takes places.

MST2-RASSF protein-protein interactions through SARAH domains.

The detailed, atomistic-level understanding of molecular signaling along the tumor-suppressive Hippo signaling pathway that controls tissue homeostasis by balancing cell proliferation and death through apoptosis is a promising avenue for the discovery of novel anticancer drug targets. The activation of kinases such as Mammalian STE20-Like Protein Kinases 1 and 2 (MST1 and MST2)-modulated through both homo- and heterodimerization (e.g. interactions with Ras association domain family, RASSF, enzymes)-is a key upstream event in this pathway and remains poorly understood. On the other hand, RASSFs (such as RASSF1A or RASSF5) act as important apoptosis activators and tumor suppressors, although their exact regulatory roles are also unclear. We present recent molecular studies of signaling along the Ras-RASSF-MST pathway, which controls growth and apoptosis in eukaryotic cells, including a variety of modern molecular modeling and simulation techniques. Using recently available structural information, we discuss the complex regulatory scenario according to which RASSFs perform dual signaling functions, either preventing or promoting MST2 activation, and thus control cell apoptosis. Here, we focus on recent studies highlighting the special role being played by the specific interactions between the helical Salvador/RASSF/Hippo (SARAH) domains of MST2 and RASSF1a or RASSF5 enzymes. These studies are crucial for integrating atomistic-level mechanistic information about the structures and conformational dynamics of interacting proteins, with information available on their system-level functions in cellular signaling.

Improvement of Anion Transport Systems by Modulation of Chalcogen Interactions: The influence of solvent.

A series of potential anion transporters, dithieno[3,2-b;2',3'-d]thiophenes (DTT), involving anion-chalcogen interactions have been studied by analyzing the interaction energy, geometry, and charge transfer. It was found that gas phase calculations show very negative interaction energies with short anion-chalcogen distances, but when solvent effects are considered, the interaction energy values decreased drastically concomitantly with an elongation on the interatomic distances. To enhance the chalcogen interaction between the DTT derivatives and the anion, increasing the anion transporter capacity, bisisothioazole moiety was considered; i.e., the σ-hole of the chalcogen atom was modulated by substitution of the adjacent carbon by a nitrogen atom in the S-C axis, increasing the depth of the σ-hole and therefore the interaction between the chalcogen and anion. Finally, different anions were analyzed within the complexes, finding that F- and NO3- would be the best candidates to form complexes and possibly displace other anions such as Cl- or Br-.

Synthesis and Cytotoxicity Studies of Novel NHC*-Gold(I) Complexes Derived from Lepidiline A.

Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3⁻5), p-mercaptobenzoate derivatives (12⁻14) and N-acetyl-l-cysteine derivatives (15⁻17). All complexes were synthesised in good yields of 57⁻78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7topo breast cancer, HCT-116wt, and p53 knockout mutant HCT-116-/- colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7topo cell line with 3 displaying an IC50 of 0.28 µM ± 0.03 µM. Complexes incorporating a Au⁻S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6⁻311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh3.

SARAH Domain-Mediated MST2-RASSF Dimeric Interactions.

RASSF enzymes act as key apoptosis activators and tumor suppressors, being downregulated in many human cancers, although their exact regulatory roles remain unknown. A key downstream event in the RASSF pathway is the regulation of MST kinases, which are main effectors of RASSF-induced apoptosis. The regulation of MST1/2 includes both homo- and heterodimerization, mediated by helical SARAH domains, though the underlying molecular interaction mechanism is unclear. Here, we study the interactions between RASSF1A, RASSF5, and MST2 SARAH domains by using both atomistic molecular simulation techniques and experiments. We construct and study models of MST2 homodimers and MST2-RASSF SARAH heterodimers, and we identify the factors that control their high molecular stability. In addition, we also analyze both computationally and experimentally the interactions of MST2 SARAH domains with a series of synthetic peptides particularly designed to bind to it, and hope that our approach can be used to address some of the challenging problems in designing new anti-cancer drugs.

Conformational studies of Gram-negative bacterial quorum sensing 3-oxo N-acyl homoserine lactone molecules.

In their 1H NMR spectra in CDCl3 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide NH proton when compared to the parent N-acyl homoserine lactones (AHLs). NMR spectroscopic and DFT calculation studies have shown that this is most likely due to the presence of a stabilising intramolecular H-bond from the NH to the 3-oxo group. The 1H NMR spectra also show evidence for the enol tautomers and that the amount of enol present for a range of OHLs is 4.1-4.5% in CDCl3 and 6.5-7.2% in CD3CN. In contrast, DFT calculations show that the lowest energy enol tautomer and the keto tautomer are of equal energy in the gas phase, but that the keto tautomer is more stable in chloroform, acetonitrile and water solution. The calculations also show that there is no evidence for any n→π∗ or C5H-bonding interactions being present in either the lowest energy keto or enol tautomer of the OHLs in solution or the gas phase, which is in contrast to the reported solid-state structure.

Modulation of in:out and out:out conformations in [X.X'.X''] phosphatranes by Lewis acids.

A theoretical study of [X.X'.X'']phosphatrane:Lewis acid complexes has been carried out in order to analyze how the in:out and out:out conformations can be modulated by the interaction with Lewis acids (LA). It has been found that in:out structures are more stable in larger systems i.e. in [4.4.3]:LA and [4.4.4]:LA than in [3.3.3]:LA and [4.3.3]:LA. The results obtained for the relative energies in conjunction with electron density properties showed that upon complexation, in:out conformers become more stable with the increasing acidity of the corresponding Lewis acid. In fact, the binding energies found for in:out complexes are larger than those obtained for out:out complexes. The complexes with the largest relative energy favoring the in:out structure correspond to those with charged Lewis acids, followed by the complexes with ClF. In all cases, the complexes are cooperative, reaching a maximum value of 168.5 kJ mol-1 for the [4.3.3]:F+ complex.