Boronic acids : structural and mechanistic studies and application as macromolecular sensing systems

textBoronic acids, particularly those that carry an ortho-aminomethyl group, have been extensively utilized in the field of molecular recognition in recent years thanks to their ability to reversibly bind to a wide variety of polyol substrates. They have been shown to form cyclic boronate esters rapidly upon reaction with 1,2- and 1,3-diols, catechols, carbohydrates and hydroxycarboxylic acids, making them attractive as potential sensing units. While they have found broad application in this forum, the mechanism by which they work is still up for debate. This work begins in Chapter 1 with a review of the fundamentals of ¹¹B NMR spectroscopy and its application on the analysis of boronic acid-containing systems. The focus of Chapter 2 turns toward systems with an o-iminomethylphenylboronic acid moiety. This species can be formed easily through a three-component assembly, though physical understanding of this complex lags behind. With the fundamentals of ¹¹B NMR spectroscopy detailed previously, the results obtained when utilizing this technique to study both the structure and mode of interaction in these species will be presented. In Chapter 3 we give a comprehensive review of the data and conclusions that have been published by different groups about one of the most successful fluorescent sugar sensors of this kind, first introduced by Seiji Shinkai in 1994. Additionally, it delineates the experimental results obtained by our group when attempting to answer some of the remaining questions. In Chapter 4 we report the use of the aforementioned multi-component assembly as an enantioselective sensor for α-chiral primary amines. Using circular dichroism, the ee% of these analytes could be accurately determined with this system. Additionally, enantio- and chemodiscrimination was possible by employing chemometric tools like PCA and LDA. Finally, Chapter 5 is a compilation of efforts to expand the use of these sensing systems into synthetic organic chemistry research labs. In collaboration with Xumu Zhang at Rutgers University, we have implemented a previously developed system to analyze the product of an asymmetric hydrogenation of an imine to create a chiral amine. A proof of concept study on a novel automated circular dichroism plate reader prototype aimed to increasing sample throughput was completed at New York University with Professor Bart Kahr.Chemistr

Structural and thermodynamic analysis of a three-component assembly forming <i>ortho</i>-iminophenylboronate esters

Structural studies of a three-component assembly - a host and two distinct guests - were carried out using a combination of 11B and 1H NMR. In aprotic solvent, the imino group that forms ortho to the boronic acid or boronate ester group can form a dative N-B bond. In protic solvent, a molecule of solvent inserts between the nitrogen and boron atoms, partially ionizing the solvent molecule. Additionally, 11B NMR was used in combination with a seventh-order polynomial to calculate five binding constants for each of the individual steps in protic solvent. Comparison of these binding constants was used to establish positive cooperativity in the binding of the two guests.</p

Metallotexaphyrins as MRI-Active Catalytic Antioxidants for Neurodegenerative Disease: A Study on Alzheimer’s Disease

The complex etiology of neurodegeneration continues to stifle efforts to develop effective therapeutics. New agents elucidating key pathways causing neurodegeneration might serve to increase our understanding and potentially lead to improved treatments. Here, we demonstrate that a water soluble manganese(II) texaphyrin (MMn) is a suitable magnetic resonance imaging (MRI) contrast agent for detecting larger amyloid beta constructs. The imaging potential of MMn was inferred on the basis of in vitro studies and in vivo detection in Alzheimer's disease C. elegans models using MRI and ICP-MS. In vitro antioxidant and cellular-based assays provide support for the notion that this porphyrin analogue shows promise as a therapeutic agent able to mitigate the oxidative and nitrative toxic effects considered causal in neurodegeneration. The present report marks the first elaboration of an MRI-active metalloantioxidant that confers diagnostic and therapeutic benefit in Alzheimer's disease models without conjugation of a radioisotope, targeting moiety, or therapeutic payload

Next-Generation TLC: A Quantitative Platform for Parallel Spotting and Imaging

A high-throughput screening approach for simultaneous analysis and quantification of the percent conversion of up to 48 reactions has been developed using a thin-layer chromatography (TLC) imaging method. As a test-bed reaction, we monitored 48 thiol conjugate additions to a Meldrum's acid derivative (1) in parallel using TLC. The TLC elutions were imaged using a cell phone and a LEGO brick-constructed UV/vis light box. Further, a spotting device was constructed from LEGO bricks that allows simple transfer of the samples from a well-plate to the TLC plate. Using software that was developed to detect "blobs" and report their intensity, we were able to quantitatively determine the extent of completion of the 48 reactions with one analysis

The mechanisms of boronate ester formation and fluorescent turn-on in ortho-aminomethylphenylboronic acids

ortho-Aminomethylphenylboronic acids are used in receptors for carbohydrates and various other compounds containing vicinal diols. The presence of the o-aminomethyl group enhances the affinity towards diols at neutral pH, and the manner in which this group plays this role has been a topic of debate. Further, the aminomethyl group is believed to be involved in the turn-on of the emission properties of appended fluorophores upon diol binding. In this treatise, a uniform picture emerges for the role of this group: it primarily acts as an electron-withdrawing group that lowers the pK(a) of the neighbouring boronic acid thereby facilitating diol binding at neutral pH. The amine appears to play no role in the modulation of the fluorescence of appended fluorophores in the protic-solvent-inserted form of the boronic acid/boronate ester. Instead, fluorescence turn-on can be consistently tied to vibrational-coupled excited-state relaxation (a loose-bolt effect). Overall, this Review unifies and discusses the existing data as of 2019 whilst also highlighting why o-aminomethyl groups are so widely used, and the role they play in carbohydrate sensing using phenylboronic acids

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Circular Dichroism of Multi-Component Assemblies for Chiral Amine Recognition and Rapid ee Determination

Upon mixing a chiral amine, enantiopure BINOL, and o-formyl phenyl boronic acid, the three components assemble efficiently and rapidly into chiral host-guest structures that produce distinct circular dichroism signals for each enantiomer of the amine. Employing BINOL and two derivatives to create an array of receptors, the CD signals resulting from several a-chiral primary amines were processed by principal component analysis and linear discriminant analysis to give satisfactory discrimination of the amines studied. Not only was the system able to differentiate the analytes chemoselectively and enantioselectively, but it also allowed for the rapid determination of chiral amineNational Institutes of Health GM77437Welch Foundation F-1151Chemistr

An Equipment Hub for Managing a Small Town and a Complex Machine

Effective maintenance of the accelerators’ complex is vital for CERN’s mission. While this work is highly dependent on operational planning and constraints, it also needs to be coordinated with the maintenance of the infrastructure where the complex is embedded. The nature and degree of the logistics problems that arise from this interdependence cannot be handled by partial, decoupled solutions from each of the stakeholders. CERN’s Enterprise Asset Management system is the central hub where all relevant data about equipment and its maintenance is kept. It is also where data and documents about the manufacturing, installation, safety inspection, radiation measurements, disposal, etc. of the scientific equipment reside. This hub allows the effective sharing of consistent equipment data, accessed by a large number of people and systems, and supplies a wide range of interfaces – ranging from the user in the field with no access to a desktop computer, to scheduling systems that need to interact with it through Web services; this is achieved by means of a series of systems, tools and mechanisms, all dedicated to different needs but working on the same data and sharing common policies