Analysis of Content of 2-Oxoacids in Rat Brain Extracts Using High-Performance Liquid Chromatography

Biochemistry (Moscow) - 2-Oxoacids are involved in a number of important metabolic processes and can be used as biomarkers in some human diseases. A new optimized method for quantification of...     

Barriers to Industrial Symbiosis: Insights from the Use of a Maturity Grid

The concept of industrial symbiosis (IS) over the last 20 years has become a well‐recognized approach for environmental improvements at the regional level. Many technical solutions for waste and by‐product material, water, and energy reuse between neighboring industries (so‐called synergies) have been discovered and applied in the IS examples from all over the world. However, the potential for uptake of new synergies in the regions is often limited by a range of nontechnical barriers. These barriers include environmental regulation, lack of cooperation and trust between industries in the area, economic barriers, and lack of information sharing. Although several approaches to help identify and overcome some of the nontechnical barriers were examined, no methodology was found that systematically assessed and tracked the barriers to guide the progress of IS development. This article presents a new tool—IS maturity grid—to tackle this issue in the regional IS studies. The tool helps monitor and assess the level of regional industrial collaboration and also indicates a potential path for further improvements and development in an industrial region, depending on where that region currently lies in the grid. The application of the developed tool to the Gladstone industrial region of Queensland, Australia, is presented in the article. It showed that Gladstone is at the third (active) stage of five stages of maturity, with cooperation and trust among industries the strongest characteristic and information barriers the characteristic for greatest improvement.     

Chemical Composition of Pinus sibirica (Pinaceae)

Siberian pine (Pinus sibirica), also known as Siberian cedar pine and Siberian cedar, is an important plant that has been long used as a source of natural compounds and materials (wood, needles, soft resin, turpentine, colophony). Its chemical composition has been studied well enough; however, to our surprise, no articles that compile the phytochemical data have been published so far. Presumably, this is due to the fact that most of the studies were published in journals difficult to access and not indexed by search systems. This review, for the first time, presents a systematic compilation of available data of secondary metabolites occurring in the needles, shoots, bark, wood, seeds, and oleoresin of Pinus sibirica.     

Structural simplification of bioactive natural products with multicomponent synthesis. 4. 4H-Pyrano-[2,3-b]naphthoquinones with anticancer activity

4H-Pyrano-[2,3-b]naphthoquinone is a structural motif commonly found in natural products manifesting anticancer activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed a compound library based on this heterocyclic scaffold. We found that several library members displayed low micromolar antiproliferative activity and induced apoptosis in human cancer cells. Selected compounds showed promising activity against cancer cell lines resistant to proapoptotic stimuli, demonstrating their potential in treating cancers with dismal prognoses.     

Optimization and structure–activity relationships of a series of potent inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as novel antimicrobial agents

A novel series of hydrazones were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK has been identified as one of the most highly connected ‘hub proteins’ in MRSA. PK has been shown to be critical for bacterial survival which makes it a potential target for development of novel antibiotics and the high degree of connectivity implies it should be very sensitive to mutations and thus less able to develop resistance. PK is not unique to bacteria and thus a critical requirement for such a PK inhibitor would be that it does not inhibit the homologous human enzyme(s) at therapeutic concentrations. Several MRSA PK inhibitors (including 8d) were identified using in silico screening combined with enzyme assays and were found to be selective for bacterial enzyme compared to four human PK isoforms (M1, M2, R and L). However these lead compounds did not show significant inhibitory activity for MRSA growth presumably due to poor bacterial cell penetration. Structure–activity relationship (SAR) studies were carried out on 8d and led us to discover more potent compounds with enzyme inhibiting activities in the low nanomolar range and some were found to effectively inhibit bacteria growth in culture with minimum inhibitory concentrations (MIC) as low as 1 μg/mL. These inhibitors bind in two elongated flat clefts found at the minor interfaces in the homo-tetrameric enzyme complex and the observed SAR is in keeping with the size and electronic constraints of these binding sites. Access to the corresponding sites in the human enzyme is blocked.     

Design and synthesis of novel N-sulfonyl-2-indole carboxamides as potent PPAR-gamma binding agents with potential application to the treatment of osteoporosis

The synthesis and structure-activity relationships of a novel series of N-sulfonyl-2-indole carboxamides that bind to peroxisome proliferator-activated receptor gamma (PPAR-gamma) are reported. Chemical optimization of the series led to the identification of 4q (IC(50)=50 nM) as a potent binding agent of PPAR-gamma. Also reported is preliminary cell based data suggesting the use of these compounds in the treatment of osteoporosis.     

Molecular recognition in the P2Y14 receptor: Probing the structurally permissive terminal sugar moiety of uridine-5′-diphosphoglucose

The P2Y₁₄ receptor, a nucleotide signaling protein, is activated by uridine-5′-diphosphoglucose 1 and other uracil nucleotides. We have determined that the glucose moiety of 1 is the most structurally permissive region for designing analogues of this P2Y₁₄ agonist. For example, the carboxylate group of uridine-5′-diphosphoglucuronic acid proved to be suitable for flexible substitution by chain extension through an amide linkage. Functionalized congeners containing terminal 2-acylaminoethylamides prepared by this strategy retained P2Y₁₄ activity, and molecular modeling predicted close proximity of this chain to the second extracellular loop of the receptor. In addition, replacement of glucose with other sugars did not diminish P2Y₁₄ potency. For example, the [5′′]ribose derivative had an EC₅₀ of 0.24 μM. Selective monofluorination of the glucose moiety indicated a role for the 2′′- and 6′′-hydroxyl groups of 1 in receptor recognition. The β-glucoside was twofold less potent than the native α-isomer, but methylene replacement of the 1′′-oxygen abolished activity. Replacement of the ribose ring system with cyclopentyl or rigid bicyclo[3.1.0]hexane groups abolished activity. Uridine-5′-diphosphoglucose also activates the P2Y₂ receptor, but the 2-thio analogue and several of the potent modified-glucose analogues were P2Y₁₄-selective.     

Spatio‐temporal control of neural epithelial cell migration and epithelium‐to‐mesenchyme transition during avian neural tube development

As opposed to the neural crest, the neural epithelium is generally viewed as a static and cohesive structure. Here, using an ex vivo system free of the environmental influences and physical constraints encountered in the embryo, we show that neural epithelial cells are on the contrary intrinsically motile, although they do not undergo spontaneous epithelium‐to‐mesenchyme transition and display molecular and cellular characteristics distinct from those of neural crest cells. However, they can be instructed to undergo epithelium‐to‐mesenchyme conversion independently of the acquisition of neural crest traits. Migration potentialities of neural epithelial cells are transient and are progressively restricted during neural tube development. Restriction of cell migration is irreversible and can be in part accounted for by increase in N‐cadherin in cellular junctions and in cell polarity. In conclusion, our study reveals that the neural epithelium is a highly flexible tissue in which cells are maintained cohesive under the control of a combination of extrinsic factors and physical constraints.