Spatially Formed Tenacious Nickel-Supported Bimetallic Catalysts for CO2 Methanation under Conventional and Induction Heating.

The paper introduces spatially stable Ni-supported bimetallic catalysts for CO2 methanation. The catalysts are a combination of sintered nickel mesh or wool fibers and nanometal particles, such as Au, Pd, Re, or Ru. The preparation involves the nickel wool or mesh forming and sintering into a stable shape and then impregnating them with metal nanoparticles generated by a silica matrix digestion method. This procedure can be scaled up for commercial use. The catalyst candidates were analyzed using SEM, XRD, and EDXRF and tested in a fixed-bed flow reactor. The best results were obtained with the Ru/Ni-wool combination, which yields nearly 100% conversion at 248 °C, with the onset of reaction at 186 °C. When we tested this catalyst under inductive heating, the highest conversion was observed already at 194 °C.

A Thiosemicarbazone Derivative as a Booster in Photodynamic Therapy-A Way to Improve the Therapeutic Effect.

Photodynamic therapy is one of the most patient friendly and promising anticancer therapies. The active ingredient is irradiated protoporphyrin IX, which is produced in the body that transfers energy to the oxygen-triggering phototoxic reaction. This effect could be enhanced by using iron chelators, which inhibit the final step of heme biosynthesis, thereby increasing the protoporphyrin IX concentration. In the presented work, we studied thiosemicarbazone derivative, which is a universal enhancer of the phototoxic effect. We examined several genes that are involved in the transport of the heme substrates and heme itself. The results indicate that despite an elevated level of ABCG2, which is responsible for the PpIX efflux, its concentration in a cell is sufficient to trigger a photodynamic reaction. This effect was not observed for 5-ALA alone. The analyzed cell lines differed in the scale of the effect and a correlation with the PpIX accumulation was observed. Additionally, an increased activation of the iron transporter MFNR1 was also detected, which indicated that the regulation of iron transport is essential in PDT.

Unsupervised Learning in Drug Design from Self-Organization to Deep Chemistry.

The availability of computers has brought novel prospects in drug design. Neural networks (NN) were an early tool that cheminformatics tested for converting data into drugs. However, the initial interest faded for almost two decades. The recent success of Deep Learning (DL) has inspired a renaissance of neural networks for their potential application in deep chemistry. DL targets direct data analysis without any human intervention. Although back-propagation NN is the main algorithm in the DL that is currently being used, unsupervised learning can be even more efficient. We review self-organizing maps (SOM) in mapping molecular representations from the 1990s to the current deep chemistry. We discovered the enormous efficiency of SOM not only for features that could be expected by humans, but also for those that are not trivial to human chemists. We reviewed the DL projects in the current literature, especially unsupervised architectures. DL appears to be efficient in pattern recognition (Deep Face) or chess (Deep Blue). However, an efficient deep chemistry is still a matter for the future. This is because the availability of measured property data in chemistry is still limited.

Functional and Material Properties in Nanocatalyst Design: A Data Handling and Sharing Problem.

(1) Background: Properties and descriptors are two forms of molecular in silico representations. Properties can be further divided into functional, e.g., catalyst or drug activity, and material, e.g., X-ray crystal data. Millions of real measured functional property records are available for drugs or drug candidates in online databases. In contrast, there is not a single database that registers a real conversion, TON or TOF data for catalysts. All of the data are molecular descriptors or material properties, which are mainly of a calculation origin. (2) Results: Here, we explain the reason for this. We reviewed the data handling and sharing problems in the design and discovery of catalyst candidates particularly, material informatics and catalyst design, structural coding, data collection and validation, infrastructure for catalyst design and the online databases for catalyst design. (3) Conclusions: Material design requires a property prediction step. This can only be achieved based on the registered real property measurement. In reality, in catalyst design and discovery, we can observe either a severe functional property deficit or even property famine.

Enhancing the CO2 capturing ability in leaf via xenobiotic auxin uptake.

Plants are masterpieces of evolution that is based on carbon chemistry. In particular, plant leaves are biosynthetic factories able to convert CO2 into carbohydrates and oxygen. It is worth noting that mimicking the efficiency of a natural plant and natural leaf is still a challenge for contemporary chemistry. We can even better realize this when we notice that a plant and an industrial factory are equivalent in meaning. On the other hand, green technologies are under development in a quest for the artificial leaf. If we could modify the synthetic pathways in leaves, we could also design green chemistry schemes in natural leaves to produce useful chemicals or to digest wastes or toxins. Specifically, can we intensify the potential for capturing atmospheric CO2 in leaves? Auxins are plant hormones that control the growth and development of plants. Herein, we determined whether we could efficiently transport xenobiotic auxin into leaves and if so, whether this supply could enhance the metabolism and CO2 capturing ability. By exploring a series of dioxolanes as potential enhancers of auxin transport, we discovered for the first time that a small molecular compound, 2,2-dimethyl-1,3-dioxolane (DMD), enhances the xenobiotic auxin transport to leaves, which boosts the metabolism that is measured by H2O2 production as well as CO2 capturing ability in leaves.

Live cell imaging by 3-imino-(2-phenol)-1,8-naphthalimides: The effect of ex vivo hydrolysis.

A series of 3-amino-N-substituted-1,8-naphthalimides and their salicylic Schiff base derivatives were synthesized. The structure of the obtained compounds was confirmed using 1H and 13C NMR, FT-IR spectroscopy and elemental analysis and COSY and HMQC for the representative molecules. The photophysical (UV-Vis, PL) and biological properties of all of the prepared compounds were studied. It was found that the amine with the n-hexyl group in EtOH had the highest PL quantum yield (Ф = 85%) compared to the others. Moreover, the chelating properties of the azomethines with the n-hexyl group (1a, 1b, 1c) were tested against various cations (Al3+, Ba2+, Co2+, Cu2+, Cr3+, Fe2+, Fe3+, Mn2+, Ni2+, Pb2+, Sr2+ and Zn2+) in an acetonitrile, acetone and PBS/AC mixture. Compounds that contained the electron withdrawing groups (-Br, -I) had the ability to chelate most of the studied cations, while the unsubstituted derivative chelated only the trivalent cations such as Al3+, Cr3+ and Fe3+ in acetonitrile. The effect of the environment on the keto-enol tautomeric equilibrium was also demonstrated, especially in the case of the derivative with a bromine atom. The biological studies showed that the tested molecules had no cytotoxicity. Additionally, the ability to image intracellular organelles such as the mitochondria and endoplasmic reticulum was revealed. The crucial role of the hydrolysis of imines for cellular imaging was presented.

Impact of thiosemicarbazones on the accumulation of PpIX and the expression of the associated genes.

Thiosemicarbazone derivatives are known for their broad biological activity including their antitumor potency. The aim of the current study was to examine the effect of a novel series of non-toxic iron chelators on the accumulation of protoporphyrin IX after external 5-aminolevulonic acid administration. From this series we selected one the most promising derivative which causes a pronounced increase in the concentration of protoporphyrin IX. The increase of the photosensitizer concentration is necessary for the trigger the efficient therapeutic effect of the photodynamic reaction. For selected compound 2 we performed an examination of a panel of the genes that are involved in the heme biosynthesis and degradation. Results indicated the crucial roles of ferrochelatase and heme oxygenase in the described processes. Surprisingly, there was a strict dependence on the type of the tested cell line. A decrease in the expression of the two aforementioned enzymes after incubation with compound 2 and 5-aminolevulonic acid is a commonly known fact and we detected this trend for the MCF-7 and HCT 116 cell lines. However, we noticed the upregulation of the tested targets for the Hs683 cells. These unconventional results prompted us to do a more in-depth analysis of the described processes. In conclusion, we found that compound 2 is a novel, highly effective booster of photodynamic therapy that has prospective applications.

Ligand potency - an essential estimator for drug design: between intuition, misinterpretation and serendipity.

This is a review of developments in the field of potency, which is an essential estimator for drug design. We discuss the basic concepts of research and discovery, focusing on how misinterpretation in this area, - but also intuition and serendipity, which are common in drug design - helped us to pave a bumpy road towards better drugs. How far we still are from this goal can be seen in the Eroom law, which states that the efficiency of pharma research and development is decreasing. At the same time, pharma bestsellers are getting older.

Ligand Potency, Efficiency and Drug-likeness: A Story of Intuition, Misinterpretation and Serendipity.

The concept of ligand potency is briefly discussed here as well as why this is still a challenge for its complete comprehension. In this context, we explain also the meaning of ligand efficiency (LE), which has been greeted with both enthusiasm and criticism among the drug design audience. A full understanding of LE requires the complex interpretation of the potency concept presenting the uncertainty similar to this of the Zeno paradox. In reality, the efficiency of LE is caused by the high degree of preference for slim pharma drug candidates.

Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study.

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure⁻activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host⁻target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.

Anticancer activity of the thiosemicarbazones that are based on di-2-pyridine ketone and quinoline moiety.

Thiosemicarbazones (TSC) are a subclass of iron-chelating agents that are believed to have an anticancer activity. The high potential for the application of this compound class can be illustrated by a fact that three TSC have entered clinical trials. The ability to chelate metal ions results in several biochemical changes in the cellular metabolism and growth. An important factor that determines the antitumor activity of TSC is a level of iron regulatory proteins and the antioxidant potential that is specific for each type of cancer cell. However, despite the increasing interest in TSC, their mechanism of anticancer activity is still unclear. For a more effective and rational design, it is crucial to determine and describe the abovementioned issues. In this report, we describe a series of new TSC that are designed on the four main structural scaffolds. The anticancer activity of these compounds was evaluated against a panel of cancer cell lines including colon and breast cancers and gliomas. Special attention was paid to the metal-dependent proteins. The impact of the tested TSC on the cell cycle and redox homeostasis was also determined. These results confirm a p53-independent mechanism of apoptosis.

A Study of Catalytic Oxidation of a Library of C2 to C4 Alcohols in the Presence of Nanogold.

The classical stoichiometric oxidation of alcohols is an important tool in contemporary organic chemistry. However, it still requires huge modifications in order to comply with the principles of green chemistry. The use of toxic chemicals, hazardous organic solvents, and the large amounts of toxic wastes that result from the reactions are a few examples of the problems that must be solved. Nanogold alone or conjugated with palladium were supported on different carriers (SiO2, C) and investigated in order to evaluate their catalytic potential for environmentally friendly alcohol oxidation under solvent-free and base-free conditions in the presence H2O2 as a clean oxidant. We tested different levels of Au loading (0.1⁻1.2% wt.) and different active catalytic site forms (monometallic Au or bimetallic Au⁻Pd sites). This provided new insights on how the structure of the Au-dispersions affected their catalytic performance. Importantly, the examination of the catalytic performance of the resulting catalysts was oriented toward a broad scope of alcohols, including those that are the most resistant to oxidation-the primary aliphatic alcohols. Surprisingly, the studies proved that Au/SiO2 at a level of Au loading as low as 0.1% wt. appeared to be efficient and prospective catalytic system for the green oxidation of alcohol. Most importantly, the results revealed that 0.1% Au/SiO2 might be the catalyst of choice with a wide scope of utility in the green oxidation of various structurally different alcohols as well as the non-activated aliphatic ones.

The role of oxidative stress in activity of anticancer thiosemicarbazones.

Thiosemicarbazones are chelators of transition metals such as iron or copper whose anticancer potency is intensively investigated. Although two compounds from this class have entered clinical trials, their precise mechanism of action is still unknown. Recent studies have suggested the mobilization of the iron ions from a cell, as well as the inhibition of ribonucleotide reductase, and the formation of reactive oxygen species. The complexity and vague nature of this mechanism not only impedes a more rational design of novel compounds, but also the further development of those that are highly active that are already in the preclinical phase. In the current work, a series of highly active thiosemicarbazones was studied for their antiproliferative activity in vitro. Our experiments indicate that these complexes have ionophoric properties and redox activity. They appeared to be very effective generating reactive oxygen species and deregulating the antioxidative potential of a cell. Moreover, the genes that are responsible for antioxidant capacity were considerably deregulated, which led to the induction of apoptosis and cell cycle arrest. On the other hand, good intercalating properties of the studied compounds may explain their ability to cleave DNA strands and to also poison related enzymes through the formation of reactive oxygen species. These findings may help to explain the particularly high selectivity that they have over normal cells, which generally have a stronger redox equilibrium.

Piperazinyl fragment improves anticancer activity of Triapine.

A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial prerequisite for the high activity of the previously obtained TSC compounds-DpC and Dp44mT. We tested the important physicochemical characteristics of the novel compounds L1-L12. The studied ligands are neutral at physiological pH, which allows them to permeate cell membranes and bind cellular Fe pools more readily than less lipid-soluble ligands, e.g. DFO. The selectivity and anti-cancer activity of the novel TSCs were examined in a variety of cancer cell types. In general, the novel compounds demonstrated the greatest promise as anti-cancer agents with both a potent and selective anti-proliferative activity. We investigated the mechanism of action more deeply, and revealed that studied compounds inhibit the cell cycle (G1/S phase). Additionally we detected apoptosis, which is dependent on cell line's specific genetic profile. Accordingly, structure-activity relationship studies suggest that the combination of the piperazine ring with Triapine allows potent and selective anticancer chelators that warrant further in vivo examination to be identified. Significantly, this study proved the importance of the di-substitution pattern of the amine N4 function.

Electrolytic copper as cheap and effective catalyst for one-pot triazole synthesis.

Electrolytic copper is a well-known form of pure, oxygen free copper that is used for industrial applications. In this work, the catalytic potential of this relatively cheap material was studied. The addition of less than 0.015 mol equivalent of copper powder effectively catalysed the one-pot synthesis of triazoles from a diverse range of organic halides and alkynes. Quantitative conversions in aqueous solvents can be achieved within minutes. The heterogenous nature of the catalyst afforded a low level of copper contamination in the products, thus meeting the rigorous criteria of the pharmaceutical industry.

Beware of ligand efficiency (LE): understanding LE data in modeling structure-activity and structure-economy relationships.

BACKGROUND: On the one hand, ligand efficiency (LE) and the binding efficiency index (BEI), which are binding properties (B) averaged versus the heavy atom count (HAC: LE) or molecular weight (MW: BEI), have recently been declared a novel universal tool for drug design. On the other hand, questions have been raised about the mathematical validity of the LE approach. RESULTS: In fact, neither the critics nor the advocates are precise enough to provide a generally understandable and accepted chemistry of the LE metrics. In particular, this refers to the puzzle of the LE trends for small and large molecules. In this paper, we explain the chemistry and mathematics of the LE type of data. Because LE is a weight metrics related to binding per gram, its hyperbolic decrease with an increasing number of heavy atoms can be easily understood by its 1/MW dependency. Accordingly, we analyzed how this influences the LE trends for ligand-target binding, economic big data or molecular descriptor data. In particular, we compared the trends for the thermodynamic ∆G data of a series of ligands that interact with 14 different target classes, which were extracted from the BindingDB database with the market prices of a commercial compound library of ca. 2.5 mln synthetic building blocks. CONCLUSIONS: An interpretation of LE and BEI that clearly explains the observed trends for these parameters are presented here for the first time. Accordingly, we show that the main misunderstanding of the chemical meaning of the BEI and LE parameters is their interpretation as molecular descriptors that are connected with a single molecule, while binding is a statistical effect in which a population of ligands limits the formation of ligand-receptor complexes. Therefore, LE (BEI) should not be interpreted as a molecular (physicochemical) descriptor that is connected with a single molecule but as a property (binding per gram). Accordingly, the puzzle of the surprising behavior of LE is explained by the 1/MW dependency. This effect clearly explains the hyperbolic LE trend not as a real increase in binding potency but as a physical limitation due to the different population of ligands with different MWs in a 1 g sample available for the formation of ligand-receptor complexes. Graphical abstract .

The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot †.

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, "Drug Synthesis and Analysis," meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.

Iron Chelators and Exogenic Photosensitizers. Synergy through Oxidative Stress Gene Expression.

In non-invasive anticancer photodynamic therapy (PDT), a nontoxic photosensitizer (PS), which is activated by visible light, is used as a magic bullet that selectively destroys cancer cells. Recently, we described the combined therapy of 5-aminolevulinic acid (ALA-PDT) with thiosemicarbazone (TSC), i.e. an iron-chelating agent. This resulted in a strong synergistic effect. Herein, we investigated a novel strategy using a combination of PDT consist of the xenobiotic-porphyrin type PS with TSC. We observed a synergistic effect for all of the pairs of TSC-PS. This approach can be rationalized by the fact that both chlorin and TSC can affect the generation of reactive oxygen species (ROS). In order to elucidate the plausible mechanism of action, we also combined the investigated PSs with DFO, which forms complexes that are redox inactive. We detected a slight antagonism or additivity for this combination. This may suggest that the ability of an iron chelator (IC) to participate in the production of ROS and the generation of oxidative stress is important.

Between Descriptors and Properties: Understanding the Ligand Efficiency Trends for G Protein-Coupled Receptor and Kinase Structure-Activity Data Sets.

The chemical meaning of the ligand efficiency (LE) metrics is explained in this paper using a large G protein-coupled receptor (GPCR) and kinase structure-activity (IC50, Ki) data set. Although there is a controversy in the literature regarding both the mathematical validity and the performance of LE, it is in common use as an early estimator for drug optimization. Apparently, the numerous con arguments are not convincing enough. We show here for the first time that the main misunderstanding of the chemical meaning of LE is its interpretation as a molecular descriptor connected with a single molecule. Instead, LE should be interpreted as a statistical property. We show that the LE, which is designed as a regression of a binding property on the heavy atom count (HAC), is correlated to the reciprocal of the molecular weight because of Avogadro statistics. This indicates that the hyperbolic model of LE is basically a consequence of a nonbinding effect, an increase in the number of ligands that are available to a receptor for smaller molecules, and not a real increase in the binding potency for a single HAC as interpreted in the literature. Accordingly, we need to revisit and carefully reevaluate LE-based molecular comparisons.

The Eighth Central European Conference "Chemistry towards Biology": Snapshot.

The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on August 28-September 1, 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered "Chemistry towards Biology", meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.