Hydrolysis of alkyl cyanoacrylate and ethoxycarbonylpropenoylphosphonate polymers

The polymers of ethyl α-cyanopropenoate (widely known as cyanoacrylate) and dimethyl (α-ethoxycarbonyl)propenoylphosphonate have been hydrolyzed and their rates of degradation to formaldehyde have been compared. The phosphate polymer produced much less formaldehyde than the cyanopropenoate polymer as required for an improved surgical adhesive. In a comparative study, the rate of aqueous hydrolysis of a high molecular weight cyanoacrylate polymer differed from a previous report. The nature and the hydrolytic properties of the end groups in the two types of polymer are discussed.     

Models of steroid binding based on the minimum deviation of structurally assigned 13C NMR spectra analysis (MiDSASA)

This paper develops a quantitative k-nearest neighbors modeling technique. The technique is used to demonstrate that a compound's biological binding activity to a receptor can be calculated from the minimum of the square root of the sum of squared deviations (SSSD) of a structurally assigned chemical shift on a template between the unknown compound to be predicted and a set of known compounds with known activities. When building models of biological activity, nonlinear relationships are built into the input training data. If a model is developed by selecting only compounds with minimum structurally assigned chemical shift deviations from the unknown compound, some of the nonlinear relationships can be removed. The smaller the total chemical shift deviation between a compound with known activity and another compound with unknown activity, the more likely it will have similar biological, chemical, and physical properties. This means that a model can be produced without rigorous statistics or neural networks. This technique is similar to structure-activity relationship (SAR) modeling, but instead of relying on substructure fragments to produce a model, this new model is based on minimum chemical shift differences on those substructure fragments. We refer to this method as minimum deviation of structurally assigned spectra analysis (MiDSASA) modeling. Modeling by the minimum deviation concept can be applied to other chemoinformatic data analyses such as metabolite concentrations in metabolic pathways for metabolomics research. A MiDSASA template model for 30 steroids binding the corticosterone binding globulin based on the activity factors of the two nearest compounds had a correlation of 0.88. A MiDSASA template model for 50 steroids binding the aromatse enzyme based on the average activity of the four nearest compounds had a correlation of 0.71.     

Fake molecular-orbital calculations

The FAKE method of approximate molecular-orbital calculations is presented and illustrated by application to a number of molecules. The method is of the extended Huckel type but uses accurately computed kinetic-energy matrix elements and avoids scale factors of the Wolfsberg—Helmholtz type. It also includes neighbor-atom charge effects and single-center off-diagonal matrix elements. These features permit FAKE occupied-orbital energies and charge distributions to come into close agreement with corresponding ab initio quantities.     

Cyclic Voltammetry in a Perfluorocarbon Emulsion Blood Substitute

Cyclic voltammetry in a perfluorocarbon emulsion based blood substitute (PEBS) was evaluated. The intent was to determine how PEBS affects the voltammetry of four representative electroactive compounds: potassium ferricyanide, ruthenium(II) trisbipyridine (rutris), hydroquinone, and 2,6‐dichloroindophenol (DCIP). Voltammograms in 0–20% PEBS‐Tris buffer mixtures are affected by PEBS, but reasonably well‐defined voltammograms are obtained in as much as 20% v/v. This report also shows that PEBS has only a small effect on amperometric detection of the reaction between DCIP and nicotinamide adenine dinucleotide (NADH), which has importance in clinical homogeneous immunoassays. Results support continued exploration of voltammetry/amperometry for quantitative analysis in this medium.     

General deoxyribozyme-catalyzed synthesis of native 3'-5' RNA linkages

An elusive goal for nucleic acid enzymology has been deoxyribozymes that ligate RNA rapidly, sequence-generally, with formation of native 3'-5' linkages, and in preparatively useful yield. Using in vitro selection, we have identified Mg2+- and Zn2+-dependent deoxyribozymes that simultaneously fulfill all four of these criteria. The new deoxyribozymes operate under practical incubation conditions and have modest RNA substrate sequence requirements, specifically D downward arrowRA for 9DB1 and A downward arrowR for 7DE5 (D = A, G, or U; R = A or G). These requirements are comparable to those of deoxyribozymes such as 10-23 and 8-17, which are already widely used as biochemical tools for RNA cleavage. We anticipate that the 9DB1 and 7DE5 deoxyribozymes will find immediate practical application for RNA ligation.     

The Bohlmann-Rahtz route to functionalised pyridine scaffolds and their use in library synthesis

The Bohlmann-Rahtz reaction has been used to prepare 2,3,6-trisubstituted pyridines suitable for use in library synthesis. The synthesis of piperidine substituted nicotinic acid derivative 9 has been optimised and carried out on a large scale to give ca. 500 g of scaffold which was used in the generation of the pyridine library 11.     

Structural properties of ultra-small thorium and uranium dioxide nanoparticles embedded in a covalent organic framework

We report the structural properties of ultra-small ThO₂ and UO₂ nanoparticles (NPs), which were synthesized without strong binding surface ligands by employing a covalent organic framework (COF-5) as an inert template. The resultant NPs were used to observe how structural properties are affected by decreasing grain size within bulk actinide oxides, which has implications for understanding the behavior of nuclear fuel materials. Through a comprehensive characterization strategy, we gain insight regarding how structure at the NP surface differs from the interior. Characterization using electron microscopy and small-angle X-ray scattering indicates that growth of the ThO₂ and UO₂ NPs was confined by the pores of the COF template, resulting in sub-3 nm particles. X-ray absorption fine structure spectroscopy results indicate that the NPs are best described as ThO₂ and UO₂ materials with unpassivated surfaces. The surface layers of these particles compensate for high surface energy by exhibiting a broader distribution of Th–O and U–O bond distances despite retaining average bond lengths that are characteristic of bulk ThO₂ and UO₂. The combined synthesis and physical characterization efforts provide a detailed picture of actinide oxide structure at the nanoscale, which remains highly underexplored compared to transition metal counterparts.

ThO₂ and UO₂ nanoparticles synthesized using a COF-5 template exhibit unpassivated surfaces and provide insight into nanoscale properties of actinides.     

Synthesis of the B-ring of FR182877. Investigation of the reactions of 6-fumaryl 1,3,8-nonatrienes

Investigation of the intramolecular Diels-Alder reactions of 6-fumaryl 1,3,8-nonatrienes, substituted at the C5 by a vinyl group, to afford the B-ring of FR182877 are reported. The synthesis of the required 1,3,8-nonatriene was achieved quickly and in high yield. 6-Fumaryl 1,3,8-nonatrienes substituted at the C5 by a vinyl group were found to undergo competing tandem sigmatropic rearrangement/Diels-Alder cyclisation when heated under standard Diels-Alder cyclisation conditions. This rearrangement became the exclusive pathway when the reaction was performed in the presence of a Lewis acid. As expected from modeling studies, the major intramolecular Diels-Alder cyclisation product was the desired exo-trans adduct, which was required for the synthesis of FR182877. Intrigued by the rearrangements, a number of alterations were made to the 1,3,8-nonatriene. Replacement of the fumaryl group by an acetyl group resulted in the diminished reactivity of the 1,3,8-nonatriene with neither rearrangements nor cycloadditions observed. Variation of the C5 substituent was found to be very important in determining the π-diastereoselectivity of the Diels-Alder cyclisation.     

Chemoproteomic profiling of kinases in live cells using electrophilic sulfonyl triazole probes

Sulfonyl-triazoles are a new class of electrophiles that mediate covalent reaction with tyrosine residues on proteins through sulfur-triazole exchange (SuTEx) chemistry. Recent studies demonstrate the broad utility and tunability of SuTEx chemistry for chemical proteomics and protein ligand discovery. Here, we present a strategy for mapping protein interaction networks of structurally complex binding elements using functionalized SuTEx probes. We show that the triazole leaving group (LG) can serve as a releasable linker for embedding hydrophobic fragments to direct molecular recognition while permitting efficient proteome-wide identification of binding sites in live cells. We synthesized a series of SuTEx probes functionalized with a lipid kinase fragment binder for discovery of ligandable tyrosines residing in catalytic and regulatory domains of protein and metabolic kinases in live cells. We performed competition studies with kinase inhibitors and substrates to demonstrate that probe binding is occurring in an activity-dependent manner. Our functional studies led to discovery of probe-modified sites within the C2 domain that were important for downregulation of protein kinase C-alpha in response to phorbol ester activation. Our proof of concept studies highlight the triazole LG of SuTEx probes as a traceless linker for locating protein binding sites targeted by complex recognition elements in live cells.

Sulfonyl-triazole probes modified with a kinase recognition element are developed for live cell activity-based profiling to identify tyrosine sites located in catalytic and regulatory domains that are important for kinase function.