Probing Reactivity with External Forces: The Case of Nitroacetamides in Water.

Many computational methods have been applied to interpret and predict changes in reactivity by slight modifications of a given molecular scaffold. We describe a novel and simple method based on approximate density-functional theory of valence electrons that can be applied within a large high-performance computational infrastructure to probe such changes using a statistical sample of molecular configurations, including the solvent. All the used computational tools are fully open-source.

Primary nitro compounds: progress in the synthesis of isoxazoles by condensation with aldehydes or activated ketones.

Among the known strategies directed towards the synthesis of isoxazole derivatives, the reactions of aldehydes with primary nitro compounds deserve a comprehensive treatment, including the historical development as well as the more recent applications. The reactions of aldehydes with primary nitro compounds in a 1 : 2 molar ratio have been shown to lead to isoxazoline--oxides or isoxazole derivatives, β-dinitro derivatives. Several modifications of the process allowed the formation of products bearing substituents at various positions of the heterocyclic ring with control of regioselectivity.

Probing the Structure of Toxic Amyloid-β Oligomers with Electron Spin Resonance and Molecular Modeling.

Structural models of the toxic species involved in the development of Alzheimer's disease are of utmost importance to understand the molecular mechanism and to describe early biomarkers of the disease. Among toxic species, soluble oligomers of amyloid-β (Aβ) peptides are particularly important, because they are responsible for spreading cell damages over brain regions, thus rapidly impairing brain functions. In this work we obtain structural information on a carefully prepared Aβ(1-42) sample, representing a toxic state for cell cultures, by combining electron spin resonance spectroscopy and computational models.

Multiwalled Carbon Nanotubes for Combination Therapy: a Biodistribution and Efficacy Pilot Study.

A drug delivery system (DDS) for combined therapy, based on a short oxidized multiwalled carbon nanotube, is reported. It was prepared exploiting a synthetic approach which allowed loading of two drugs, doxorubicin and metformin, the targeting agent biotin and a radiolabeling tag, to enable labeling with Ga-68 or Cu-64 in order to perform an extensive biodistribution study by PET/CT. The DDS biodistribution profile changes with different administration methods.

Understanding the Exceptional Properties of Nitroacetamides in Water: A Computational Model Including the Solvent.

Proton transfer in water involving C⁻H bonds is a challenge and nitro compounds have been studied for many years as good examples. The effect of substituents on acidity of protons geminal to the nitro group is exploited here with new p K a measurements and electronic structure models, the latter including explicit water environment. Substituents with the amide moiety display an exceptional combination of acidity and solubility in water.

Conjugate addition versus cycloaddition/condensation of nitro compounds in water: selectivity, acid-base catalysis, and induction period.

Nitroacetates and nitroacetamides react in water as in chloroform with electron-deficient dipolarophiles to give condensation or conjugate addition products under base catalysis. In general, high selectivity towards condensation is observed in water, with shorter induction periods than in chloroform. In water, condensations slowly occur even without base; kinetic profiles evidence the catalytic effect of the base, which should be related to the conversion into the tautomer nitronic acid.

Acid-base-catalysed condensation reaction in water: isoxazolines and isoxazoles from nitroacetates and dipolarophiles.

Base-catalysed condensation reactions of nitroacetic esters with dipolarophiles to give isoxazole derivatives proceed faster, and often with higher yields, in the presence of water than in organic solvents such as chloroform. Kinetic profiles show that induction times are greatly reduced when the reaction is performed "in water" or "on water". Any specificity of the base related to H-bonding ability observed in chloroform is lost in water: all bases either organic or inorganic give the same result that is simply depending on concentration.

Michael additions versus cycloaddition condensations with ethyl nitroacetate and electron-deficient olefins.

Ethyl nitroacetate (1) reacts with electron-poor olefins in the presence of a base to give either the Michael adducts 3 or the isoxazoline cycloadducts 4, resulting from water elimination. The proportions of the two products depend on the reaction conditions and change in the course of the process. Kinetic profiles for the two reactions show that the cycloaddition-condensations require long induction times that dramatically decrease upon addition of a copper salt to the catalytic system: the drops in the induction time cause increases in the proportion of cycloadducts 4, which are often the sole reaction products.

Synthesis of 4,5-dihydroisoxazoles by condensation of primary nitro compounds with alkenes by using a copper/base catalytic system.

A new procedure for the synthesis of 4.5-dihydroisoxazoles by condensation of primary nitro compounds with olefins by using a copper/base catalytic system is described. The catalytic effect of copper(II) salts is evidenced by comparison of the reaction rates.

Parallel synthesis of an amide library based on the 6,8-dioxa-3-azabicyclo[3.2.1]octane scaffold by direct aminolysis of methyl esters.

An efficient synthesis of unsubstituted and substituted amides based on the 6,8-dioxa-3-azabicyclo[3.2.1]octane scaffold is described.

Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors.

Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12).

Inhibition of rabbit brain 4-aminobutyrate transaminase by some taurine analogues: a kinetic analysis.

The use of the antiepileptic drug, 4-aminobutyrate transaminase (GABA-T) inhibitor vigabatrin (VIGA), has been recently cautioned because it is associated to irreversible field defects from damage of the retina. Since novel GABA-T inhibitors might prove useful in epilepsy or other CNS pathologies as VIGA substitutes, the aim of the present investigation was to characterize the biochemical properties of some taurine analogues (TA) previously shown to act as GABA-T inhibitors. These include (+/-)piperidine-3-sulfonic acid (PSA), 2-aminoethylphosphonic acid (AEP), (+/-)2-acetylaminocyclohexane sulfonic acid (ATAHS) and 2-aminobenzenesulfonate (ANSA).

A new bicyclic dipeptide isostere with pyrrolizidinone skeleton.

The synthesis of a new conformationally constrained Gly-(s-cis)Pro Turn Mimetic (GPTM) in both racemic and enantiomerically pure forms and their incorporation into peptides 18, 21, and 24 are reported. The synthetic strategy adopted to assemble the bicyclic pyrrolizidinone skeleton is based on the 1,3-dipolar cycloaddition of the cyclic nitrone 4a derived from proline and acrylamide, followed by a reductive cleavage/cyclization domino process. The enantiomerically pure GPTMs are obtained by synthesis and separation of diastereomeric intermediates containing (1R)-1-phenylethylamine as chiral auxiliary.

A specific taurine recognition site in the rabbit brain is responsible for taurine effects on thermoregulation.

(1) Taurine and GABA are recognized as endogenous cryogens. In a previous study, some structural analogues of taurine, namely 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) have been shown to displace [(3)H]taurine binding from rabbit brain synaptic membrane preparations, without interacting either with GABA-ergic systems, nor with taurine uptake mechanism, thus behaving like direct taurinergic agents. (2) To answer the question whether the role of taurine as an endogenous cryogen depends on the activation of GABA receptors or that of specific taurine receptor(s), taurine or the above structural analogues were injected intracerebroventricularly in conscious, restrained rabbits singularly or in combination and their effects on rectal (RT)- and ear-skin temperature and gross motor behavior (GMB) were monitored.

Interactions of taurine and structurally related analogues with the GABAergic system and taurine binding sites of rabbit brain.

1. The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. 2.