Evidence for Ruthenium(II) Peralkene Complexes as Catalytic Species during the Isomerization of Terminal Alkenes in Solution.

The isomerization (chain-walking) reaction of terminal to internal alkenes is catalyzed by part-per-million amounts of practically any Ru source when the reaction is carried out with a neat terminal alkene. Here, we provide evidence that the soluble starting Ru sources evolve to catalytically active peralkene Ru(II) species under reaction conditions. These species may also explain the isomerization products found during other Ru-catalyzed alkene processes, i.e., alkene metathesis reactions. A Finke-Watzky mechanism for catalyst formation is consistent with the evidence obtained.

Removal of an Azo Dye from Wastewater through the Use of Two Technologies: Magnetic Cyclodextrin Polymers and Pulsed Light.

Water pollution by dyes is a huge environmental problem; there is a necessity to produce new decolorization methods that are effective, cost-attractive, and acceptable in industrial use. Magnetic cyclodextrin polymers offer the advantage of easy separation from the dye solution. In this work, the ß-CD-EPI-magnetic (ß-cyclodextrin-epichlorohydrin) polymer was synthesized, characterized, and tested for removal of the azo dye Direct Red 83:1 from water, and the fraction of non-adsorbed dye was degraded by an advanced oxidation process. The polymer was characterized in terms of the particle size distribution and surface morphology (FE-SEM), elemental analysis (EA), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), infrared spectrophotometry (IR), and X-ray powder diffraction (XRD). The reported results hint that 0.5 g and pH 5.0 were the best conditions to carry out both kinetic and isotherm models. A 30 min contact time was needed to reach equilibrium with a qmax of 32.0 mg/g. The results indicated that the pseudo-second-order and intraparticle diffusion models were involved in the assembly of Direct Red 83:1 onto the magnetic adsorbent. Regarding the isotherms discussed, the Freundlich model correctly reproduced the experimental data so that adsorption was confirmed to take place onto heterogeneous surfaces. The calculation of the thermodynamic parameters further demonstrates the spontaneous character of the adsorption phenomena (ΔG° = −27,556.9 J/mol) and endothermic phenomena (ΔH° = 8757.1 J/mol) at 25 °C. Furthermore, a good reusability of the polymer was evidenced after six cycles of regeneration, with a negligible decline in the adsorption extent (10%) regarding its initial capacity. Finally, the residual dye in solution after treatment with magnetic adsorbents was degraded by using an advanced oxidation process (AOP) with pulsed light and hydrogen peroxide (343 mg/L); >90% of the dye was degraded after receiving a fluence of 118 J/cm2; the discoloration followed a pseudo first-order kinetics where the degradation rate was 0.0196 cm2/J. The newly synthesized ß-CD-EPI-magnetic polymer exhibited good adsorption properties and separability from water which, when complemented with a pulsed light-AOP, may offer a good alternative to remove dyes such as Direct Red 83:1 from water. It allows for the reuse of both the polymer and the dye in the dyeing process.

Theoretical Prediction of Dual-Potency Anti-Tumor Agents: Combination of Oxoplatin with Other FDA-Approved Oncology Drugs.

Although Pt(II)-based drugs are widely used to treat cancer, very few molecules have been approved for routine use in chemotherapy due to their side-effects on healthy tissues. A new approach to reducing the toxicity of these drugs is generating a prodrug by increasing the oxidation state of the metallic center to Pt(IV), a less reactive form that is only activated once it enters a cell. We used theoretical tools to combine the parent Pt(IV) prodrug, oxoplatin, with the most recent FDA-approved anti-cancer drug set published by the National Institute of Health (NIH). The only prerequisite imposed for the latter was the presence of one carboxylic group in the structure, a chemical feature that ensures a link to the coordination sphere via a simple esterification procedure. Our calculations led to a series of bifunctional prodrugs ranked according to their relative stabilities and activation profiles. Of all the designed molecules, the combination of oxoplatin with aminolevulinic acid as the bioactive ligand emerged as the most promising strategy by which to design enhanced dual-potency oncology drugs.

Intermolecular Carbonyl-olefin Metathesis with Vinyl Ethers Catalyzed by Homogeneous and Solid Acids in Flow.

The carbonyl-olefin metathesis reaction has experienced significant advances in the last seven years with new catalysts and reaction protocols. However, most of these procedures involve soluble catalysts for intramolecular reactions in batch. Herein, we show that recoverable, inexpensive, easy to handle, non-toxic, and widely available simple solid acids, such as the aluminosilicate montmorillonite, can catalyze the intermolecular carbonyl-olefin metathesis of aromatic ketones and aldehydes with vinyl ethers in-flow, to give alkenes with complete trans stereoselectivity on multi-gram scale and high yields. Experimental and computational data support a mechanism based on a carbocation-induced Grob fragmentation. These results open the way for the industrial implementation of carbonyl-olefin metathesis over solid catalysts in continuous mode, which is still the origin and main application of the parent alkene-alkene cross-metathesis.

Tuning the Optical Properties of Novel Antitumoral Drugs Based on Cyclometalated Iridium(III) Complexes.

Most of the current efforts in drug discovery are devoted to the design of molecules able to mitigate side effects by concentrating the biological action in the targeted tissue. One promising strategy is photodynamic therapy, which is based on the in situ generation of reactive singlet oxygen upon radiation exposure. However, such an approach requires the use of an efficient photosensitizer. This contribution deals with the optical properties of an Ir(III) complex, [Ir(pbz)2(N^N)] (pbz = 2-phenylbenzimidazole; N^N = methyl 1-butyl-2-pyridyl-benzimidazole-5-carboxylate), which has recently been shown to exhort a strong photoactivity, but still needs further improvements to reach clinical applications. We performed density functional theory calculations at the M06, PBE0, ωB97xD, and CAM-B3LYP levels to predict the impact of introducing electron donor-acceptor groups into the nature of the lowest excited states. The simulations performed demonstrate that the presence of a NH2 at the pbz ligand and a NO2 group at the N^N ligand yield a bathochromic shift of absorption spectrum. We report the most sensitive positions to tune the optical signatures of this family of complexes.

Exposing the G-quadruplex to electric fields: the role played by telomeres in the propagation of DNA errors.

To protect their core machinery from the attack of exogenous agents, cells locate DNA in their nucleus. Nevertheless, some reactive chemical species and physical agents might reach DNA and alter its natural double helix structure. For instance, pulsed electric fields can be used to selectively rewrite the stored genetic information. However, for such modification to be effective, one needs, as a prerequisite, that the replication mechanism is not stopped by the field, so that the changes propagate over the following generations. Here, we use theoretical calculations to demonstrate that while such fields lead to permanent noncanonical Watson-Crick guanine-cytosine (GC) base pairs, the G-quadruplex motifs present in telomeres can more effectively preserve their native forms. Indeed, G-quadruplexes "resist" the perturbations induced by field strengths going up to 60 × 10-4 a.u., a figure constituting the upper limit before the complete destruction of the double helix architecture. Since the induced errors in the DNA base pairs are not transcribed into the telomeres, electric fields can indeed be used as a source of selective mutations in the genetic code.

Assessing the importance of proton transfer reactions in DNA.

Although engineered by millions of years of evolution, the cellular machinery is not flawless, and errors regularly appear during DNA replication. The subsequent alteration of the stored genetic message results in a mutation and might be the starting point of important health disorders. The question therefore is what causes DNA mutations? All living organisms are constantly exposed to a number of external agents such as free radicals and to radiation, which may lead to induced mutations. There are also mutations happening without invoking the action of any exogenous element, the so-called spontaneous mutations. The former can be partially controlled by avoiding exposure to high-risk environments, while the latter are more intriguing because their origin is unclear and difficult to determine. As noted by Watson and Crick when they first discovered the DNA structure, the correct replication of DNA rests on the assumption that the base pairs remain in their most stable, canonical form. However, protons along the interbase hydrogen-bond network are not static entities. They can in fact interchange their positions in DNA bases through proton transfer (PT) reactions before strands unwind, giving rise to noncanonical structures defined as rare tautomers. The importance of these rare tautomers was also cleverly anticipated by Watson and Crick and some years later claimed by Löwdin to be a source of spontaneous mutations. In Watson and Crick's words: "It would be of interest to know the precise difference in free energy between the various tautomeric forms under physiological conditions." Unfortunately, rare tautomeric forms are very difficult to detect, so no direct and accurate free energy measure has been discerned. In contrast, theoretical chemistry is making good progress toward the quantification of PT reactions in DNA and their biological consequences. This Account touches upon the theoretical studies devoted to appraising the importance of rare tautomers as promoters of spontaneous mutations. We focus in particular on the crucial role played by the biological environment on DNA stability. It has now been demonstrated that valuable macroscopic predictions require not only highly accurate theories but also refined chemical models. Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations performed on short but complete DNA sequence fragments emerge in this context as the most adequate tools. In addition, these methods can be used to quantify the effect of different external agents on the PT tautomeric equilibria and, eventually, to conveniently handle them. This is the case for the possible alteration of the naturally observed mutation rate by exposure to intense electric fields. Theoretical predictions envision in this respect promising applications of ultrashort electric pulses in medicine to selectively modify the mutated/canonical ratio in DNA.

How DNA is damaged by external electric fields: selective mutation vs. random degradation.

DNA is constantly exposed to exogenous agents that randomly damage the genetic code. However, external perturbations might also be used to induce malignant cell death if the mutation processes are controlled. The present communication reports a set of parameters allowing DNA mutation through the use of intense external electric fields. This is a step towards the design of pulsed electric field therapy for genetic diseases.

Few-layer black phosphorus enables nitrogen fixation under ambient conditions.

Nitrogen (N2) fixation is a key reaction in biological and industrial chemistry, which does not occur spontaneously under ambient conditions but often depends on very specific catalysts and harsh reaction processes. Here we show that exposing exfoliated black phosphorus to the open air triggers, concomitantly, the oxidation of the two-dimensional (2D) material and the fixation of up to 100 parts per million (0.01%) of N2 on the surface. The fixation also occurs in pristine non-exfoliated material. Besides, other allotropic forms of phosphorus, like red P, also fixes N2 during ambient oxidation, suggesting that the N2 fixation process is intrinsic with phosphorus oxidation and does not depend on the chemical structure or the dimensionality of the solid. Despite the low amounts of N2 fixed, this serendipitous discovery could have fundamental implications on the chemistry and environmental stability of phosphorous and the design of related catalysts for N2 fixation.

Development of Chitosan Polysaccharide-Based Magnetic Gel for Direct Red 83:1 Removal from Water.

Water pollution caused by dyes is a significant environmental issue, necessitating the development of effective, cost-efficient decolorization methods suitable for industrial use. In this study, a Chitosan-Fe polymeric gel was synthesized, characterized, and tested for removing the azo dye Direct Red 83:1 from water. The polymeric magnetic chitosan was analyzed using various techniques: Field Emission Scanning Electron Microscopy (FE-SEM) revealed a porous structure, Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) demonstrated the thermal stability, Infrared Spectrophotometry (IR) indicated the successful coordination of iron at the C3 position, and X-ray Powder Diffraction (XRD) confirmed the crystalline nature of the polymeric structure. Optimal conditions for kinetic and isotherm models were found at 1 g and pH 7.0. Adsorption behavior of Direct Red 83:1 onto magnetic chitosan gel beads was studied through kinetic tests and isotherm curves. The maximum adsorption capacity was 17.46 mg/g (qmax). The adsorption process followed pseudo-second-order kinetics (R2 = 0.999) and fit the Temkin isotherm (R2 = 0.946), suggesting heterogeneous surface adsorption. The newly synthesized Chitosan-Fe polymeric gel demonstrated good adsorption properties and facilitated easy separation of purified water.

Conformational changes of ß-carotene and zeaxanthin immersed in a model membrane through atomistic molecular dynamics simulations.

In this work, we investigate systems formed by ß-carotene and zeaxanthin embedded separately in a model lipid bilayer of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) through molecular dynamics (MD) simulations. The study is conducted using an all-atoms model and by analyzing the structural changes that occur at both the carotenoid molecule and the membrane during the simulations. We concentrate specifically on the conformation of the conjugated chain, given the relevance that this feature has in modulating the spectroscopic and antioxidant properties of the carotenoids. The force fields of the carotenoids are parametrized accordingly in order to reproduce the rotation potentials of the conjugated chains calculated using quantum DFT methods. A model to quantify the effective conjugated chain length is presented. The MD simulations are carried out using the parameters adjusted for the carotenoids along with those provided by the CHARMM36 force field for the lipids of the membrane. A differentiating dynamic behavior of ß-carotene and zeaxanthin within the bilayer is observed in the simulations, which is analyzed in detail through umbrella sampling techniques. This behavior is driven basically by the interactions of the lipid polar heads with the hydroxyl groups of zeaxanthin, which are absent in ß-carotene. These interactions influence the carotenoid orientation, modify the conformational distribution of the dihedral angles of the conjugated chain significantly, and specifically distort the membrane structure.

Antioxidant properties of ß-carotene isomers and their role in photosystems: insights from Ab initio simulations.

In this work we investigate the effect of cis isomerizations and conformational changes on the antioxidant activity of ß-carotene, one of the most important pigments in nature. The electrodonating (ω(-)) and electroaccepting (ω(+)) powers of the most relevant isomers of ß-carotene are first evaluated in polar and nonpolar solvents using density functional theory (DFT), and these quantities are then used to establish an antioxidant scale of the isomers. The electrodonating power, which is directly related to the antioxidant activity, is shown to provide a very good correlation with the experimental data. Next, we compute the intermediate twisted structures of the ß-carotene isomers generated by partial rotation of every single bond in the polyenic chain. The electrodonating and electroaccepting powers are evaluated for each of these intermediate structures along with their maximum absorption wavelengths, which are computed using time-dependent DFT (TD-DFT). The trends observed for both the electrodonating power and the maximum absorption wavelength can be rationalized in terms of the effective conjugated chain length of the structure resulting from single bond rotations. The results obtained are used to analyze the conformational distribution of ß-carotene in the well-resolved photosystem I (PS-I) of purple cyanobacteria. It is then shown that the isomers present in this photosystem are those having the lowest calculated relative energies and that those with enhanced antioxidant activity are preferentially located in the inner core of the protein complex.

Cytotoxic sub-nanometer aqueous platinum clusters as potential antitumoral agents.

Ligand-free sub-nanometer metal clusters (MCs) of Pt, Ir, Rh, Au and Cu, are prepared here in neat water and used as extremely active (nM) antitumoral agents for HeLa and A2870 cells. The preparation just consists of adding the biocompatible polymer ethylene-vinyl alcohol (EVOH) to an aqueous solution of the corresponding metal salt, to give liters of a MC solution after filtration of the polymer. Since the MC solution is composed of just neat metal atoms and water, the intrinsic antitumoral activity of the different sub-nanometer metal clusters can now fairly be evaluated. Pt clusters show an IC50 of 0.48 µM for HeLa and A2870 cancer cells, 23 times higher than that of cisplatin and 1000 times higher than that of Pt NPs, and this extremely high cytotoxicity also occurs for cisplatin-resistant (A2870 cis) cells, with a resistance factor of 1.4 (IC50 = 0.68 µM). Rh and Ir clusters showed an IC50 ∼ 1 µM. Combined experimental and computational studies support an enhanced internalization and cytotoxic activation.

Cyclic metal(oid) clusters control platinum-catalysed hydrosilylation reactions: from soluble to zeolite and MOF catalysts.

The Pt-catalysed addition of silanes to functional groups such as alkenes, alkynes, carbonyls and alcohols, i.e. the hydrosilylation reaction, is a fundamental transformation in industrial and academic chemistry, often claimed as the most important application of Pt catalysts in solution. However, the exact nature of the Pt active species and its mechanism of action is not well understood yet, particularly regarding regioselectivity. Here, experimental and computational studies together with an ad hoc graphical method show that the hydroaddition of alkynes proceeds through Pt-Si-H clusters of 3-5 atoms (metal(oid) association) in parts per million amounts (ppm), which decrease the energy of the transition state and direct the regioselectivity of the reaction. Based on these findings, new extremely-active (ppm) microporous solid catalysts for the hydrosilylation of alkynes, alkenes and alcohols have been developed, paving the way for more environmentally-benign industrial applications.

Size and Flexibility Define the Inhibition of the H3N2 Influenza Endonuclease Enzyme by Calix[n]arenes.

Inhibition of H3N2 influenza PA endonuclease activity by a panel of anionic calix[n]arenes and ß-cyclodextrin sulfate has been studied. The joint experimental and theoretical results reveal that the larger, more flexible and highly water-soluble sulfonato-calix[n]arenes have high inhibitory activity, with para-sulfonato-calix[8]arene, SC8, having an IC50 value of 6.4 µM. Molecular docking calculations show the SC8 can interact at both the polyanion binding site and also the catalytic site of H3N2 influenza PA endonuclease.

Visual detection of fluoride ion based on ICT mechanism.

A novel chemosensor (H3NTS) has been designed for a fast and accurate detection of F- in acetonitrile medium. The UV-Vis, 1H, 13C NMR experiments and computational calculations demonstrate that H3NTS probe offers a potential colorimetric sensor for discriminating F- among other relevant anions. The detection limit is as low as 6 µM and a reversible colorimetric switch could be devised by sequential addition of F-/Ca2+. The promising application of H3NTS is also confirmed in real examples where the concentration of F- is a critical parameter, e.g., commercial toothpaste, paper strip and gel form analysis of samples.

Advances in distributed computing with modern drug discovery.

INTRODUCTION: Computational chemistry dramatically accelerates the drug discovery process and high-performance computing (HPC) can be used to speed up the most expensive calculations. Supporting a local HPC infrastructure is both costly and time-consuming, and, therefore, many research groups are moving from in-house solutions to remote-distributed computing platforms. Areas covered: The authors focus on the use of distributed technologies, solutions, and infrastructures to gain access to HPC capabilities, software tools, and datasets to run the complex simulations required in computational drug discovery (CDD). Expert opinion: The use of computational tools can decrease the time to market of new drugs. HPC has a crucial role in handling the complex algorithms and large volumes of data required to achieve specificity and avoid undesirable side-effects. Distributed computing environments have clear advantages over in-house solutions in terms of cost and sustainability. The use of infrastructures relying on virtualization reduces set-up costs. Distributed computing resources can be difficult to access, although web-based solutions are becoming increasingly available. There is a trade-off between cost-effectiveness and accessibility in using on-demand computing resources rather than free/academic resources. Graphics processing unit computing, with its outstanding parallel computing power, is becoming increasingly important.

Antibodies as Carrier Molecules: Encapsulating Anti-Inflammatory Drugs inside Herceptine.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in about a third of breast cancer patients, with a strong involvement of the cyclooxygenase-2 (COX-2) enzyme in the tumor progress. HER2 and COX-2 are consequently potential targets for inhibiting carcionogenesis. Herceptin (trastuzumab) is an antibody that partially blocks HER2-positive cancers at their initial stage. Unfortunately, the overall response rate to the single treatment with this antibody is still modest, and therefore, it needs to be improved by combining several chemotherapeutic agents. On the other hand, nonsteroidal anti-inflammatory drugs (NSAIDs) are designed to halt COX-2 functionality, so they might also exhort an anticancer activity. In this contribution, dual Herceptin-NSAID drugs are designed using theoretical tools. More specifically, blind docking, molecular dynamics, and quantum calculations are performed to assess the stability of 14 NSAIDs embedded inside Herceptin. Our calculations reveal the feasibility of improving the antitumor activity of the parent Herceptin by designing a dual HER2-targeting with Etofenamate. That coupling mode might be used to further rationalize new clinical strategies beyond classical antibody dosages.

DFT Simulation of Structural and Optical Properties of 9-Aminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA.

In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru(II) anticancer agent and two new closely related Rh(III) and Ir(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, ωB97X, ωB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the ωB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl3) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to ωB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices.

Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo.

Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B-NS3-protease with high stability. Dexamethasone-immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV.