Enhancing reductive cleavage of aromatic carboxamides

[GRAPHICS] A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The latter undergo regiospecific cleavage of their C(O)-N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)amine in most cases in nearly quantitative yields, Examples of preparative cleavage by controlled potential electrolysis, activated aluminum, and NaBH4 are given

Easy-plane to easy-axis anisotropy switching in a Co(ii) single-ion magnet triggered by the diamagnetic lattice

Single ion magnets SIMs with large magnetic anisotropy are promising candidates for realization of single molecule based magnetic memory and qubits. Creation of materials with magnetically uncoupled spatially separated SIMs requires dilution in a diamagnetic matrix. Herein, we report that progressive dilution of paramagnetic Co II by diamagnetic Zn II in the SIM [CoxZn 1 amp; 8722;x piv 2 2 NH2 Py 2], x 1 0 beyond a threshold of 50 reveals an abrupt structural change, where the distorted tetrahedral Zn coordination structure is superimposed on the remaining Co ions, which were initially in a distorted octahedral environment. Dilution induced structure modification switches the magnetic anisotropy from easy plane D 36.7 cm amp; 8722;1 to easy axis type D amp; 8722;23.9 cm amp; 8722;1 , accompanied by a fivefold increase of the magnetic relaxation time at 2 K. Changes of the static and dynamic magnetic properties are monitored by electron paramagnetic resonance spectroscopy and AC susceptibility measurements. Complementary quantum chemical ab initio calculations quantify the influence of structural changes on the electronic structure and the magnetic anisotropy. Thus, magnetic dilution hits two goals at once, the creation of isolated magnetic centres and an improvement of their SIM propertie

Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency

INTRODUCTION: This study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB). METHODS: Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed. RESULTS: The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group. CONCLUSION: This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management

Основные направления совершенствования технологической подготовки морских инженеров

The paper contains a training structure for ship-builders which is accepted at higher educational institutions of Russian Federation. A special attention is paid to the necessity of a continuous training (in computers, machine drawing, mathematics, languages, technologies) during the whole educational process. In order to improve the educational process quality it is recommended to integrate enterprises’ resources (personnel and production) into it. The paper reveals fields of cooperation, some joint projects in tile sphere of shipbuilding to be realized in the Republic of Belarus.Приводится структура подготовки специалистов по судостроению, принятая в вузах РФ. Обращается внимание на необходимость непрерывной подготовки (компьютерной, математической, по машинной графике, языковой, технологической) в ходе учебного процесса. Для повышения качества учебного процесса рекомендуется интегрировать ресурсы предприятий (кадровые и производственные). Приводятся области сотрудничества, совместные проекты в сфере судостроения для реализации в Республике Беларусь

Promiscuous Aggregate-Based Inhibitors Promote Enzyme Unfolding

One of the leading sources of false positives in early drug discovery is the formation of organic small molecule aggregates, which inhibit enzymes nonspecifically at micromolar concentrations in aqueous solution. The molecular basis for this widespread problem remains hazy. To investigate the mechanism of inhibition at a molecular level, we determined changes in solvent accessibility that occur when an enzyme binds to an aggregate using hydrogen-deuterium exchange mass spectrometry. For AmpC beta-lactamase, binding to aggregates of the small molecule rottlerin increased the deuterium exchange of all 10 reproducibly detectable peptides, which covered 41% of the sequence of beta-lactamase. This suggested a global increase in proton accessibility upon aggregate binding, consistent with denaturation. We then investigated whether enzyme-aggregate complexes were more susceptible to proteolysis than uninhibited enzyme. For five aggregators, trypsin degradation of beta-lactamase increased substantially when beta-lactamase was inhibited by aggregates, whereas uninhibited enzyme was generally stable to digestion. Combined, these results suggest that the mechanism of action of aggregate-based inhibitors proceeds via partial protein unfolding when bound to an aggregate particle

Alpha thalassaemia-mental retardation, X linked

X-linked alpha thalassaemia mental retardation (ATR-X) syndrome in males is associated with profound developmental delay, facial dysmorphism, genital abnormalities and alpha thalassaemia. Female carriers are usually physically and intellectually normal. So far, 168 patients have been reported. Language is usually very limited. Seizures occur in about one third of the cases. While many patients are affectionate with their caregivers, some exhibit autistic-like behaviour. Patients present with facial hypotonia and a characteristic mouth. Genital abnormalities are observed in 80% of children and range from undescended testes to ambiguous genitalia. Alpha-thalassaemia is not always present. This syndrome is X-linked recessive and results from mutations in the ATRX gene. This gene encodes the widely expressed ATRX protein. ATRX mutations cause diverse changes in the pattern of DNA methylation at heterochromatic loci but it is not yet known whether this is responsible for the clinical phenotype. The diagnosis can be established by detection of alpha thalassaemia, identification of ATRX gene mutations, ATRX protein studies and X-inactivation studies. Genetic counselling can be offered to families. Management is multidisciplinary: young children must be carefully monitored for gastro-oesophageal reflux as it may cause death. A number of individuals with ATR-X are fit and well in their 30s and 40s

Drug Absorption Modeling as a Tool to Define the Strategy in Clinical Formulation Development

The purpose of this mini review is to discuss the use of physiologically-based drug absorption modeling to guide the formulation development. Following an introduction to drug absorption modeling, this article focuses on the preclinical formulation development. Case studies are presented, where the emphasis is not only the prediction of absolute exposure values, but also their change with altered input values. Sensitivity analysis of technologically relevant parameters, like the drug’s particle size, dose and solubility, is presented as the basis to define the clinical formulation strategy. Taking the concept even one step further, the article shows how the entire design space for drug absorption can be constructed. This most accurate prediction level is mainly foreseen once clinical data is available and an example is provided using mefenamic acid as a model drug. Physiologically-based modeling is expected to be more often used by formulators in the future. It has the potential to become an indispensable tool to guide the formulation development of challenging drugs, which will help minimize both risks and costs of formulation development