Search

Abstract: Pin1 is a member of the cis–trans peptidyl-prolyl isomerase family with potential anti-cancer therapeutic value. Here we report structure-based de novo design and optimization of novel Pin1 inhibitors. Without a viable lead from internal screenings, we designed a series of novel Pin1 inhibitors by interrogating and exploring a protein crystal structure of Pin1. The ligand efficiency of the initial concept molecule was optimized with integrated SBDD and parallel chemistry approaches, resulting in a more attractive lead series. [Copyright &y& Elsevier]

Abstract: The structure–activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs. [Copyright &y& Elsevier]

Abstract: The type 1 glycine transporter plays an important in regulating homeostatic glycine levels in the brain that are relevant to the activation of the NMDA receptor by the excitatory neurotransmitter glutamate. We describe herein the structure–activity relationships (SAR) of a structurally novel class of GlyT1 inhibitors following on a lead derived from high throughput screening, which shows good selectivity for GlyT1 and potent activity in elevating CSF levels of glycine. [Copyright &y& Elsevier]

Abstract: Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor. [Copyright &y& Elsevier]

It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of both the validated MDR1 and BCRP assays into our brain PBPK model has significantly improved the prediction for the brain penetration of MDR1 and BCRP substrates across species. [ABSTRACT FROM AUTHOR]

Wood adhesives are mostly synthesized from unsustainable and hazardous petrochemical-based formaldehyde. Recently, an inorganic, sustainable and environmentally friendly aluminophosphate adhesive was developed for fabricating various wood-based panels. In order to increase its competitiveness, this study developed an approach for improving the interfacial adhesion of aluminophosphate. Hence, carboxymethyl cellulose was functionalized using 3-aminopropyl triethoxysilane to alter the chemical structures of the adhesive. Thereafter, a face-centered central composite design based on response surface methodology was employed to generate the optimum production conditions for the improved plywood interfaces. Adhesive concentration and hot-press temperature were seen as the significant factors within tested limits. The most appropriate production variables were suggested with a valid predictive model for such conditions. Also, the reaction mechanisms revealed the successful altering of the aluminophosphate properties with a well-uniform adhesive surface. The results indicate that modified adhesives are more thermally stable. Furthermore, the wet bonding strength of the modified adhesive was improved above the minimum threshold (Chinese type II standard ≥0.70 MPa). Therefore, the sustainable (i.e. continuous availability of CMC) approach adopted in this research could be considered as a viable method for improving the properties of aluminophosphate adhesives. [Display omitted] • An eco-friendly and low-cost aluminophosphate adhesive was developed via functionalized carboxymethyl cellulose. • The reaction mechanism revealed successful functionalization of carboxymethyl cellulose. • The production conditions of the plywood were optimized using response surface methodology. • The fabricated plywood satisfied the basic requirements for Type II plywood. [ABSTRACT FROM AUTHOR]

Abstract: Here we report an efficient synthesis of sulfamides. 3,5-Lutidine was found to be an optimal solvent and catalyst for the reaction. The method was developed during our efforts to synthesize a series of novel FKBP-12 inhibitors in which the known ketoamide linker was replaced with sulfamide. [Copyright &y& Elsevier]

The structure-based design, chemical synthesis, and biological evaluation of bicyclic 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. An optimized compound is shown to exhibit antiviral activity when tested against a variety of HRV serotypes (EC50''s ranging from 0.037 to 0.162 μM). [Copyright &y& Elsevier]

To reduce the use of formaldehyde wood adhesives, a chemical modification of starch with chitosan was explored to prepare an adhesive film for plywood with good adhesive properties, low price, non-toxic, and convenient sizing. The effect of chitosan content of the adhesive film on the shear strength of plywood was studied. The modification mechanism and bonding mechanism of the film were analyzed by FTIR, XPS, XRD and SEM. The results showed that when the amount of chitosan was 30% of starch dry weight, the dry-wet shear strength of plywood met the requirements of Chinese national class Ⅱ plywood (≧ 0.80 MPa). FTIR and XPS analysis showed that –NH 2 in the chitosan reacted with –COOH on starch and wood surface to form amide bond, which specifies the chitosan's role as a coupling agent. XRD and SEM analysis showed that the addition of chitosan disturbed the otherwise orderly arrangement of a starch structure. The structure of the attained modified film is mostly amorphous. Sizing in the form of a adhesive film solves the disadvantage of difficulty in sizing starch adhesive. Compared with commercial adhesives on the market, this adhesive film has the advantages of low price, wide source of raw materials, non-toxic, and is expected to be a good substitute for formaldehyde adhesives on the market. • Raw starch and modifier chitosan are both sustainable resources. • Chitosan is used as a special coupling agent. • The mechanism is –NH 2 and –COOH condensation reaction. • The method of adhesive film sizing is more convenient and simple. • Adhesive film cost is lower than commercial adhesives. [ABSTRACT FROM AUTHOR]