Hybrid Classification/Regression Approach to QSAR Modeling of Stoichiometric Antiradical Capacity Assays' Endpoints

Quantitative structure-activity relationships (QSAR) are a widely used methodology allowing not only a better understanding of the mechanisms of chemical reactions, including radical scavenging, but also to predict the relevant properties of chemical compounds without their synthesis, isolation and experimental testing. Unlike the QSAR modeling of the kinetic antioxidant assays, modeling of the assays with stoichiometric endpoints depends strongly on the number of hydroxyl groups in the antioxidant molecule, as well as on some integral molecular descriptors characterizing the proportion of OH-groups able to enter and complete the radical scavenging reaction. In this work, we tested the feasibility of a "hybrid" classification/regression approach, consisting of explicit classification of individual OH-groups as involved in radical scavenging reactions, and using further the number of these OH-groups as a descriptor in simple-regression QSAR models of antiradical capacity assays with stoichiometric endpoints. A simple threshold classification based on the sum of trolox-equivalent antiradical capacity values was used, selecting OH-groups with specific radical stability- and reactivity-related electronic parameters or their combination as "active" or "inactive". We showed that this classification/regression modeling approach provides a substantial improvement of the simple-regression QSAR models over those built on the number of total phenolic OH-groups only, and yields a statistical performance similar to that of the best reported multiple-regression QSARs for antiradical capacity assays with stoichiometric endpoints.Bulgarian Ministry of Education and Science under the National Research Programme “Healthy Foods for a Strong Bio-Economy and Quality of Life”(DCM #577/17.08.2018)

Kinase signaling adaptation supports dysfunctional mitochondria in disease

Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/ AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease

The Use of Computational Methods in the Grouping and Assessment of Chemicals - Preliminary Investigations

This document presents a perspective of how computational approaches could potentially be used in the grouping and assessment of chemicals, and especially in the application of read-across and the development of chemical categories. The perspective is based on experience gained by the authors during 2006 and 2007, when the Joint Research Centre's European Chemicals Bureau was directly involved in the drafting of technical guidance on the applicability of computational methods under REACH. Some of the experience gained and ideas developed resulted from a number of research-based case studies conducted in-house during 2006 and the first half of 2007. The case studies were performed to explore the possible applications of computational methods in the assessment of chemicals and to contribute to the development of technical guidance. Not all of the methods explored and ideas developed are explicitly included in the final guidance documentation for REACH. Many of the methods are novel, and are still being refined and assessed by the scientific community. At present, many of the methods have not been tried and tested in the regulatory context. The authors therefore hope that the perspective and case studies compiled in this document, whilst not intended to serve as guidance, will nevertheless provide an input to further research efforts aimed at developing computational methods, and at exploring their potential applicability in regulatory assessment of chemicals.JRC.I.3-Toxicology and chemical substance

catena-Poly[[[triaqua­cobalt(II)]-μ-10-methyl­phenothia­zine-3,7-dicarboxyl­ato] monohydrate]

The polymeric title compound, {[Co(C15H9NO4S)(H2O)3]·H2O}n, consists of chains along [001] made up from Co2+ ions bridged by 10-methyl­phenothia­zine-3,7-dicarboxyl­ate anions. The Co2+ ion, coordinated by three O atoms from two different carboxyl­ate groups and three water mol­ecules, displays a distorted octa­hedral environment. In the crystal, π–π inter­chain inter­actions, with centroid–centroid distances of 3.656 (2) and 3.669 (2) Å between the benzene rings of the ligands, assemble the chains into sheets parallel to (100). O—H⋯O hydrogen-bonding inter­actions between the coordinating water mol­ecules and carboxyl­ate O atoms link the sheets into a three-dimensional network

Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR

Fluphenazine dihydro­chloride dimethanol solvate

In the title compound {systematic name: 1-(2-hy­droxy­eth­yl)-4-[3-(2-trifluoro­methyl-10H-phenothia­zin-10-yl)prop­yl]piperazine-1,4-diium dichloride dimethanol disolvate}, C22H28F3N3OS2+·2Cl−·2CH3OH, the dihedral angle between the planes of the two outer benzene rings of the tricyclic phenothia­zine system is 46.91 (13)°. The piperazine ring adopts a chair conformation. The crystal structure is stabilized by O—H⋯Cl, N—H⋯Cl, C—H⋯O, C—H⋯Cl and C—H⋯F hydrogen bonds and contacts

Kinase signalling adaptation supports dysfunctional mitochondria in disease

Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease

Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPAR γ

Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP) of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD) are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE) for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPARγ activation in hepatocytes and (ii) PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details

Quantitative Structure - Skin permeability Relationships

This paper reviews in silico models currently available for the prediction of skin permeability with the main focus on the quantitative structure-permeability relationship (QSPR) models. A comprehensive analysis of the main achievements in the field in the last decade is provided. In addition, the mechanistic models are discussed and comparative studies that analyse different models are discussed

Natural chain-breaking antioxidants and their synthetic analogs as modulators of oxidative stress

Oxidative stress is associated with the increased production of reactive oxygen species or with a significant decrease in the effectiveness of antioxidant enzymes and nonenzymatic defense. The penetration of oxygen and free radicals in the hydrophobic interior of biological membranes initiates radical disintegration of the hydrocarbon “tails” of the lipids. This process is known as “lipid peroxidation”, and the accumulation of the oxidation products as peroxides and the alde-hydes and acids derived from them are often used as a measure of oxidative stress levels. In total, 40 phenolic antioxidants were selected for a comparative study and analysis of their chain-breaking antioxidant activity, and thus as modulators of oxidative stress. This included natural and natural-like ortho-methoxy and ortho-hydroxy phenols, nine of them newly synthesized. Applied experimental and theoretical methods (bulk lipid autoxidation, chemiluminescence, in silico methods such as density functional theory (DFT) and quantitative structure–activity relationship ((Q)SAR) modeling) were used to clarify their structure–activity relationship. Kinetics of non-inhibited and inhibited lipid oxidation in close connection with inhibitor transformation under oxidative stress is considered. Special attention has been paid to chemical reactions resulting in the initiation of free radicals, a key stage of oxidative stress. Effects of substituents in the side chains and in the phenolic ring of hydroxylated phenols and biphenols, and the concentration were discussed