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In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV–vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound’s class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.

The mechanism of the cascade reaction between N-methylbenzamide (1) and diphenylcyclopropenone (2), catalyzed by Cp*Rh(III) (110 °C, dichloroethane), was studied using density functional theory (DFT) calculations. To assemble cyclopentene spiroisoindolenones (3) and water, 1and 2coordinate to Rh(III). Metal-catalyzed C–H activation is preferred to cyclopropenone opening by 3.7 kcal mol–1. 1acts as a proton carrier with both 1and 1H+assisting hydrogen transfer steps during the reaction. The κ-O cyclopropenone isomerizes to a η2-C═C bonding mode, the ring opens, and the first C–C bond is formed. Proton transfer from N–H to the vinyl group opens the way for obtaining the C–N bond. Two protonation steps, requiring protons from Cvinyl–H and 1H+, lead to cleavage of the C–O group and formation of water (byproduct). The second C–C bond results from an intramolecular Friedel–Crafts alkylation, in which the closest ortho-phenyl carbon binds the formal carbocation in the C5indolenone ring. The release of 3and the regeneration of the catalyst occur after two proton transfers assisted by 1and 1H+in an exergonic final step (9.3 kcal mol–1). The highest barrier corresponds to the protonation of the vinylic group during the formation of the first C–C bond (29.1 kcal mol–1).

Compounds containing halogens can form halogen bonds (XBs) with biological targets such as proteins and membranes due to their anisotropic electrostatic potential. To accurately describe this anisotropy, off-center point-charge (EP) models are commonly used in force field methods, allowing the description of XBs at the molecular mechanics and molecular dynamics level. Various EP implementations have been documented in the literature, and despite being efficient in reproducing protein–ligand geometries and sampling of XBs, it is unclear how well these EP models predict experimental properties such as hydration free energies (ΔGhyd), which are often used to validate force field performance. In this work, we report the first assessment of three EP models using alchemical free energy calculations to predict ΔGhydvalues. We show that describing the halogen anisotropy using some EP models can lead to a slight improvement in the prediction of the ΔGhydwhen compared with the models without EP, especially for the chlorinated compounds; however, this improvement is not related to the establishment of XBs but is most likely due to the improvement of the sampling of hydrogen bonds. We also highlight the importance of the choice of the EP model, especially for the iodinated molecules, since a slight tendency to improve the prediction is observed for compounds with a larger σ-hole but significantly worse results were obtained for compounds that are weaker XB donors.

In force-field methods, the usage of off-center point charges, also called extra points (EPs), is a common strategy to tackle the anisotropy of the electrostatic potential of covalently bonded halogens (X), thus allowing the description of halogen bonds (XBs) at the molecular mechanics/molecular dynamics (MM/MD) level. Diverse EP implementations exist in the literature differing on the charge sets and/or the X–EP distances. Poisson–Boltzmann and surface area (PBSA) calculations can be used to obtain solvation free energies (ΔGsolv) of small molecules, often to compute binding free energies (ΔGbind) at the MM-PBSA level. This method depends, among other parameters, on the empirical assignment of atomic radii (PB radii). Given the multiplicity of off-center point-charge models and the lack of specific PB radii for halogens compatible with such implementations, in this work, we assessed the performance of PBSA calculations for the estimation of ΔGsolvvalues in water (ΔGhyd), also conducting an optimization of the halogen PB radii (Cl, Br, and I) for each EP model. We not only expand the usage of EP models in the scope of the general AMBER force field (GAFF) but also provide the first optimized halogen PB radii in the context of the CHARMM general force field (CGenFF), thus contributing to improving the description of halogenated compounds in PBSA calculations.

Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein–ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems, thus expanding the scope of application of these interactions. Indeed, our molecular dynamics simulations show the presence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from a model phospholipid bilayer, thus supporting the existence of XB-mediated phospholipid–halogen recognition phenomena influencing the membrane insertion profile of the ligands and their orientational preferences. This represents a relevant interaction, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with potential implications in drug discovery and development, a place where such species account for a significant part of the chemical space. We also provide insights into a potential role for XBs in the water-to-membrane insertion of halogenated ligands as XBs are systematically observed during this process. Therefore, our data strongly suggest that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane partition models.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

ABSTRACTIntroduction: Halogens have a prominent role in drug design. Often used as a mean to improve ADME properties, they are also becoming a tool in protein–ligand recognition given their ability to form a non-covalent interaction, termed halogen bond, where halogens act as electrophilic species interacting with electron-rich partners. Rational drug design of halogen-bonding lead molecules requires an accurate description of halocarbon-protein complexes by computational tools though not all methods are able to tackle this non-covalent interaction.Areas covered: The authors present a review of computational methodologies that can be used to properly describe halogen bonds in the context of protein–ligand complexes, providing also insights on how these methods can be used in the context of computer-aided drug design.Expert opinion: Although in the last few years many computational tools, ranging from fast screening methods to the more expensive QM calculations, have been developed to tackle the halogen bonding phenomenon, they are not yet standard in the literature. This will eventually change as official software distributions are including support for halogen bonding in their methods. Tackling desolvation of halogenated species seems to be a good strategy to improve the accuracy of computational methods, that will be more commonly used prior to laboratory work in the future.

To model halogen-bond phenomena using classical force fields, an extra point (EP) of charge is frequently introduced at a given distance from the halogen (X) to emulate the σ-hole. The resulting molecular dynamics (MD) trajectories can be used in subsequent molecular mechanics (MM) combined with Poisson–Boltzmann and surface area calculations (PBSA) to estimate protein–ligand binding free energies (ΔGbind). While EP addition improves the MM/MD description of halogen-containing systems, its effect on the calculation of solvation free energies (ΔGsolv) using the PBSA approach is yet to be assessed. As the PBSA calculations depend, among other parameters, on the empirical assignment of radii (PB radii), a problematic issue arises, since standard halogen radii are smaller than the typical X···EP distances, thus placing the EP within the solvent dielectric. Herein, we took a common literature EP parametrization scheme, which uses X···EP = Rminand RESP charges in the context of GAFF, and performed a comprehensive study on the performance of PBSA (using three different setups) in the calculation of ΔGsolvvalues for 142 halogenated compounds (bearing Cl, Br, or I) for which the experimental values are known. By conducting an optimization (minimizing the error against experimental values), we provide a new optimized set of halogen PB radii, for each PBSA setup, that should be used in the context of the aforementioned scenario. A simultaneous optimization of PB radii and X···EP distances shows that a wide range of distance/radius pairs can be used without significant loss of accuracy, therefore laying the basis for expanding this halogen radii optimization strategy to other force fields and EP implementations. As ligand ΔGsolvestimation is an important term in the determination of protein–ligand ΔGbind, this work is particularly relevant in the framework of structure-based virtual screening and related computer-aided drug design routines.

Density functional theory (DFT) calculations were performed on clusters [Os3(CO)10(α-diimine)], for α-diimine = 2,2′-bipyridine (BPY), N-isopropyl 2-iminomethylpyridine (IMP), and N,N′-diisopropyl-l,4-diaza-1,3-butadiene (DAB), together with their spectroscopic study. This important family of clusters is known to convert upon irradiation with visible light into short-lived biradicals and long-lived zwitterions from a σπ* (SBLCT) excited state that has not been described accurately thus far by quantum mechanical calculations. On the basis of the combined DFT, UV–vis absorption, and resonance Raman data, the lowest-lying visible absorption band is assigned to a σ(Os1–Os3)-to-π*(α-diimine) CT transition, for α-diimine = bpy and IMP, and to a strongly delocalized σ(Os1–Os3)π*-to-σ*(Os1–Os3)π* transition for conjugated nonaromatic α-diimine = DAB. The DFT calculations rationalize the experimentally determined characteristics of this electronic transition in the studied series: (i) The corresponding absorption band is the dominant feature in the visible spectral region. (ii) The CT character of the electronic excitation declines from α-diimine = bpy to IMP and vanishes for DAB. (iii) The excitation energies decrease in the order α-diimine = DAB > BPY > IMP. (iv) The oscillator strength shrinks in the order α-diimine = DAB > IMP > BPY. Reference photoreaction quantum yields measured accurately for the formation of a cluster zwitterion from [Os3(CO)10(IMP)] in strongly coordinating pyridine demonstrate that the optical population of the lowest-energy 1σπ* and relaxed 3σπ* excited states in the DFT model scheme is still capable of inducing the initial homolytic Os1–Os3 σ-bond splitting, although less efficiently than the optical excitation into neighbor higher-lying electronic transitions due to a higher potential barrier for the reaction from a dissociative (σσ*) state.

Halogen bonds (XBs) are non-covalent interactions in which halogens (X), acting as electrophiles, interact with Lewis bases. XBs are able to mediate protein–ligand recognition and therefore play an important role in rational drug design. In this context, the development of molecular modeling tools that can tackle XBs is paramount. XBs are predominantly explained by the existence of a positive region on the electrostatic potential of X named the σ-hole. Typically, with molecular mechanics force fields, this region is modeled using a charged extra point (EP) linked to X along the R–X covalent bond axis. In this work, we developed the first EP-based strategy for GROMOS force fields (specifically GROMOS 54A7) using bacteriophage T4 lysozyme in complex with both iodobenzene and iodopentafluorobenzene as a prototype system. Several EP parametrization schemes were tested by adding a virtual interaction site to ligand topologies retrieved from the Automated Topology Builder (ATB) and Repository. Contrary to previous approaches using other force fields, our analysis is based on the capability of each parametrization scheme to sample XBs during MD simulations. Our results indicate that the implementation of an EP at a distance from iodine corresponding to Rminprovides a good qualitative description of XBs in MD simulations, supporting the compatibility of our approach with the GROMOS 54A7 force field.

Tetrazole/tetrazolate monocyclopentadienyliron(II) and ruthenium(II) compounds of general formulas [(η5-C5H5)M(dppe)(N4(H)CC6H4NO2)][PF6]/[(η5-C5H5)M(dppe)(N4CC6H4NO2)] were investigated for their pH-switching second-order nonlinear optical (SONLO) properties. Compounds [(η5-C5H5)M(dppe)(N4CC6H4NO2)] (M = Fe, Ru) and compound [(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)][PF6] were fully characterized by (1H-, 13C-, 31P-) NMR, cyclic voltammetry, and elemental analysis, and compounds [(η5-C5H5)Fe(dppe)(N4CC6H4NO2)] and [(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)][PF6] were further characterized by single-crystal X-ray diffraction; the synthesis of [(η5-C5H5)Fe(dppe)(N4(H)CC6H4NO2)][PF6] was unsuccessful. Time-dependent density functional theory calculations were performed using PBE0 and CAM-B3LYP functionals to evaluate the first hyperpolarizability (βtot) of the tetrazole/tetrazolate complexes and for a detailed analysis of the experimental data. Both functionals predict (i) high first hyperpolarizabilities for the tetrazolate complexes [(η5-C5H5)M(dppe)(N4CC6H4NO2)], with βtot[Ru] ≈ 1.2βtot[Fe], and (ii) a 3-fold reduction in βtot[Ru] upon protonation, in complex [(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)]+, forecasting [(η5-C5H5)Ru(dppe)(N4CC6H4NO2)]/[(η5-C5H5)Ru(dppe)(N4(H)CC6H4NO2)]+complexes as on/off, pH-switchable SONLO forms.

The anion‐templated synthesisof a halogen‐bonding catenane, which recognizes chloride and bromide ions solely by halogen bonding, is described. The catenane's ability to optically sense halide anions using fluorescence spectroscopy is demonstrated.

Die Anionentemplatsynthesedes ersten Halogenbrücken bildenden Catenans, das Chlorid‐ und Bromidionen allein über die Bildung von Halogenbrücken erkennt, wird beschrieben. Das Catenan kann zum fluoreszenzspektroskopischen Nachweis von Halogenidionen genutzt werden.

The interaction between imidazolium cations and coordinating anions is investigated through the anion‐templated assembly of interpenetrated and interlocked structures. The orientation of the imidazolium motif with respect to anion binding, and hence the hydrogen bond donor arrangement, was varied in acyclic receptors, interpenetrated assemblies, and the first mono‐imidazolium interlocked systems. Their anion recognition properties and co‐conformations were studied by solution‐phase 1H NMR investigations, solid‐state structures, molecular dynamics simulations, and density functional theory calculations. Our findings suggest that the imidazolium‐anion binding interaction is dominated by electrostatics with hydrogen‐bonding contributions having weak orientational dependence.

A new, versatile chloride‐anion‐templating synthetic pathway is exploited for the preparation of a series of eight new [2]rotaxane host molecules, including the first sulfonamide interlocked system. 1H NMR spectroscopic titration investigations demonstrate the rotaxanes’ capability to selectively recognise the chloride anion in competitive aqueous solvent media. The interlocked host’s halide binding affinity can be further enhanced and tuned through the attachment of electron‐withdrawing substituents and by increasing its positive charge. A dicationic rotaxane selectively binds chloride in 35 % water, wherein no evidence of oxoanion binding is observed. NMR spectroscopy, X‐ray structural analysis and computational molecular dynamics simulations are used to account for rotaxane formation yields, anion binding strengths and selectivity trends.

Halogenbrückenwurden genutzt, um ein verflochtenes molekulares System aufzubauen. Die Templatwirkung von Chloridionen bei der Bildung eines Pseudorotaxan aus einer 2‐Bromimidazolium‐haltigen Achse und einem Isophthalamid‐Makrocyclus (siehe Bild) ist deutlich stärker als der Effekt von Wasserstoffbrücken bei analogen Pseudorotaxanen.

The reaction between [Mo(η3-C3H5)(CO)2(NCMe)2Br] (1) and the ferrocenylamidobenzimidazole ligands FcCO(NH2benzim) (L1) and (FcCO)2(NHbenzim) (L2) led to a binuclear (2) and a trinuclear (3) Mo–Fe complex, respectively. The single-crystal X-ray structure of [Mo(η3-C3H5)(CO)2(L2)Br] [L2 = {[(η5-C5H5)Fe(η5-C5H4CO)]2(2-NH-benzimidazolyl)}] shows that L2 is coordinated to the endo Mo(η3-C3H5)(CO)2 group in a κ2-N,O-bidentate chelating fashion whereas the MoII centre displays a pseudooctahedral environment with Br occupying an equatorial position. Complex 2 was formulated as [Mo(η3-C3H5)(CO)2(L1)Br] on the basis of a combination of spectroscopic data, elemental analysis, conductivity and DFT calculations. L1 acts as a κ2-N,N-bidentate ligand. In both L1 and L2, the HOMOs are mainly localised on iron while the C=O bond(s) contribute to the LUMO(s) and the next highest energy orbitals are Fe–allyl antibonding orbitals. When the ligands bind to Mo(η3-C3H5)(CO)2Br, the greatest difference is that Mo becomes the strongest contributor to the HOMO. Electrochemical studies show that, in complex 2, no electronic interaction exists between the two ferrocenyl ligands and that the first electron has been removed from the MoII-centred HOMO. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

The complexation properties of the ligand bis(3,5-dimethylpyrazol-1-yl)methane (L) towards group 11 metals have been studied. The reaction in a 1 : 1 molar ratio with [Cu(NCMe)4]PF6or Ag(OTf) complexes gives the mononuclear [CuL(NCMe)]PF6(1), with crystallographic mirror symmetry, or dinuclear [Ag2(µ-L)2](OTf)2(2) (OTf = trifluoromethanesulfonate) in which the ligand bridges both silver centres, an unprecedented mode of coordination for this type of ligands. Compound 2crystallizes with two water molecules and forms a supramolecular structure through classical hydrogen bonding. The reaction in a 2 : 1 ratio affords in both cases the four-coordinated derivatives [ML2]X (M = Cu, X = PF6(3); Ag, X = OTf (4)). The treatment of [Ag(OTf)(PPh3)] with the ligand L gives [AgL(PPh3)]OTf (5). The gold(i) derivative [Au2(C6F5)2(µ-L)] (6) has also been obtained by reaction of L with two equivalents of [Au(C6F5)(tht)]. These complexes present a luminescent behaviour at low temperature; the emissions being mainly intraligand but enhanced after coordination of the metal. Compounds 1–4have been characterized by X-ray crystallography. DFT studies showed that, in the silver complex 2, coordination of H2O to Ag in the binuclear complex is favoured by formation of a hydrogen-bonding network, involving the triflato anion, and releasing enough energy to allow distortion of the Ag2framework.

DFT calculations suggest that the catalytic epoxidation of olefins by Mo(vi) complexes, modeled by MoO2Br2(MeNC(H)–C(H)NMe), in the presence of MeOOH, the model for tert-butyl hydroperoxide, starts with a hydrogen transfer from the peroxide to one of the terminal MoO oxygen atoms and the remaining MeOO anion binds as a seventh ligand, forming a five-membered Mo–Oα–Oβ(Me)H–O–Mo ring held together by a hydrogen bond. In the second step, a concerted approach of ethylene to the Mo–Oαbond gives rise to an intermediate containing a seven-membered Mo–C–C–Oα–Oβ(Me)H–O–Mo ring. In the final step, decomposition of the intermediate leads to the starting complex, alcohol and the epoxide. The activation energy for the addition of the olefin (second step) is the highest one, in agreement with available kinetic studies showing that the catalyst formation is not always a rate-limiting step. DFT calculations also show that the alcohol by-product (MeOH) can react with the starting complex, competing with ROOH and hence leading to the progressive catalyst poisoning, which has been observed experimentally.

This paper presents a new architecture for coordinating multiple autonomous robots in the execution of cooperative tasks. The architecture is based on the definition of a strategy that uses different tactics, setplays and roles. Roles enable to configure individual behaviour by performing specific tasks using a given set of actions. The proposed architecture allows flexible and efficient multi-robot operation in dynamic environments. The paper also presents an application of the proposed architecture to a complex domain such as middle-size robotic soccer. Our architecture is also generally enough to be applied in different robotic soccer leagues and similar multi-robot problems.

4′,4′′′-Bis(ferrocenyl)-2,2′:6′,2′′:6′′,2′′′:6′′′,2′′′′-quinquepyridine (Fc2qpy) reacts with AgOTf (OTf = trifluoromethylsulfonate) to give a complex of stoichiometry [Ag(Fc2qpy)]OTf. The crystal structure reveals a dinuclear arrangement among the cations with an Ag···Ag close contact of 3.089(2) Å. The ligands are wrapped around the silver atoms in a double helical array. Further hydrogen bonding between triflate units and the protons of the ferrocene or pyridine moieties results in a supramolecular structure. Theoretical studies confirm the existence of a weak Ag−Ag bond, and show that the dinuclear form can be more stable than the mononuclear one, when there is a favorable balance between the reorganization energy of the two quinquepyridine chains and the energy released by the formation of stronger Ag−N bonds and the new Ag−Ag interaction in the helix. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Combined picosecond transient absorption and time‐resolved infrared studies were performed, aimed at characterising low‐lying excited states of the cluster [Os3(CO)10(s‐cis‐L)] (L=cyclohexa‐1,3‐diene, 1) and monitoring the formation of its photoproducts. Theoretical (DFT and TD‐DFT) calculations on the closely related cluster with L=buta‐1,3‐diene (2′) have revealed that the low‐lying electronic transitions of these [Os3(CO)10(s‐cis‐1,3‐diene)] clusters have a predominant σ(core)π*(CO) character. From the lowest σπ* excited state, cluster 1undergoes fast OsOs(1,3‐diene) bond cleavage (τ=3.3 ps) resulting in the formation of a coordinatively unsaturated primary photoproduct (1 a) with a single CO bridge. A new insight into the structure of the transient has been obtained by DFT calculations. The cleaved OsOs(1,3‐diene) bond is bridged by the donor 1,3‐diene ligand, compensating for the electron deficiency at the neighbouring Os centre. Because of the unequal distribution of the electron density in transient 1 a, a second CO bridge is formed in 20 ps in the photoproduct [Os3(CO)8(μ‐CO)2(cyclohexa‐1,3‐diene)] (1 b). The latter compound, absorbing strongly around 630 nm, mainly regenerates the parent cluster with a lifetime of about 100 ns in hexane. Its structure, as suggested by the DFT calculations, again contains the 1,3‐diene ligand coordinated in a bridging fashion. Photoproduct 1 bcan therefore be assigned as a high‐energy coordination isomer of the parent cluster with all OsOs bonds bridged.

Oxovanadiumiv complexes with ligands derived from the reaction of salicylaldehyde with l-cysteine and with d- and d,l-penicillamine are prepared. The compounds are characterised by elemental analysis, spectroscopy UV-VIS, CD, EPR, TG, DSC and magnetic susceptibility measurements 9–295 K. We discuss several aspects related to the structure of these complexes in the solid state and in solution; in particular, the possibility of forming thiazolidine complexes, and their comparison with the characterised complexes is studied by molecular mechanics and density functional theory calculations. The solution structures depend on pH and solvent, and while with l-Cys the spectroscopic results show trends similar to those of the l-Ala and l-Ser systems up to ca.pH 8–9, where thiolate coordination starts being detected, the penicillamine system is quite distinct, namely thiolate coordination occurs for pH > 6.5. In the presence of salicylaldehyde and VIVO the desulfydration of cysteine proceeds rapidly, but no similar reaction occurs with penicillamine, although its decomposition is also activated. The DFT calculations do not indicate any energetic basis for this distinct reactivity, which possibly results from different complexes present in the Cys and Pen systems. In the cysteine system, the N-salicylidenedehydroalanine–VIVO complex Vis believed to form in an intermediate stage of the desulfydration. Further, addition of several nucleophiles to the cysteine reaction mixtures produce amino acid derivatives by a Michael-type base-catalysed addition, a result compatible with the formation of V. The products of these reactions were analysed by TLC and HPLC, and in some cases isolated.

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