A study of amino-protecting groups using the polarizable continuum model (PCM)

In order to better understand the performance of 1,2-dimethyl-5-acetyl barbituric acid (DMB) as an amino protecting group relative to 5,5-dimethylcyclohexane-1,3-dione (DMD), ab initio calculations were performed. pK_a calculations using the PCM model indicated that both molecules are more acidic in the enol form. Therefore, the protecting reaction of these molecules should involve the anions formed from the loss of a proton from the enol compounds. Contrary to what would be expected, the larger efficiency exhibited by the DMB molecule cannot be attributed to an extension of the electronic conjugation effect. In the absence of any other noticeable effect that could be responsible for the greater efficiency of the DMB molecule, we are inclined to believe that the difference could be accounted for by the presence of two independent centers of conjugation.This paper is dedicated to Jacopo Tomasi in recognition of his outstanding contribution to the field of computational chemistry in solution. The authors are honored to contribute to this volume; especially so for two of them (COS and MACN) who have the privilege of his friendship.Acknowledgements The authors would like to thank the Brazilian research agencies CNPq, CAPES and FAPERJ for the financial support. C. O. da Silva thanks the Dipartimento di Chimica e Chimica Industriale, University of Pisa, where the MCSCF calculations were performed.     

Prescribed Mean Curvature Hypersurfaces in Hn+1(-1) with Convex Planar Boundary, I

We study immersed prescribed mean curvature compact hypersurfaces with boundary in Hⁿ⁺¹(-1). When the boundary is a convex planar smooth manifold with all principal curvatures greater than 1, we solve a nonparametric Dirichlet problem and use this, together with a general flux formula, to prove a parametric uniqueness result, in the class of all immersed compact hypersurfaces with the same boundary. We specialize this result to a constant mean curvature, obtaining a characterization of totally umbilic hypersurface caps.     

Characterizing neuromorphologic alterations with additive shape functionals

The European Physical Journal B - The complexity of a neuronal cell shape is known to be related to its function. Specifically, among other indicators, a decreased complexity in the dendritic trees...     

QSAR modeling of in vitro inhibition of cytochrome P450 3A4

We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drug-enzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.     

Determination of fluoroquinolones in chicken tissues by LC-coupled electrospray ionisation and atmospheric pressure chemical ionisation

The aim of this work was to develop a method for determining seven quinolones (ciprofloxacin, danofloxacin, enrofloxacin, sarafloxacin, difloxacin, oxolinic acid and flumequine) in chicken muscle by LC coupled to MS. Two ionisation techniques, ESI and atmospheric pressure chemical ionisation (APCI) were compared using standard solutions. LOD and LOQwere determined under the optimised conditions for the two sources. The ESI was found the best for the purpose. The optimised method (LC-ESI-MS) was validated for the simultaneous analysis of the quinolones regulated by European Community in spiked chicken tissues, using norfloxacin as internal standard. Recoveries obtained varied in the range 60-109%. This method was compared with LC-UV method established previously.     

Nature of the chemical bond in protonated methane

Protonated methane, CH(5)(+), is a key reactive intermediate in hydrocarbon chemistry and a borderline case for chemical structure theory, being the simplest example of hypercoordinated carbon. Early quantum mechanical calculations predicted that the properties of this species could not be associated with only one structure, because it presents serious limitations of the Born-Oppenheimer approximation. However, ab initio molecular dynamics and diffusion Monte Carlo calculations showed that the most populated structure could be pictured as a CH(3) tripod linked to a H(2) moiety. Despite this controversy, a model for the chemical bonds involved in this ion still lacks. Here we present a modern valence bond model for the electronic structure of CH(5)(+). The chemical bond scheme derived directly from our calculations pictures this ion as H(3)C...H(2)(+). The fluxionality can be seen as the result of a proton transfer between C-H bonds. A new insight on the vibrational bands at approximately 2400 and approximately 2700 cm(-1) is suggested. Our results show that the chemical bond model can be profitably applied to such intriguing systems.     

A Faber–Krahn Inequality for Solutions of Schrödinger’s Equation on Riemannian Manifolds

We consider a bounded open set with smooth boundary \(\Omega \subset M\) in a Riemannian manifold (M, g), and suppose that there exists a non-trivial function \(u\in C({\overline{\Omega }})\) solving the problem

$$\begin{aligned} -\Delta u=V(x)u, \,\, \text{ in }\,\,\Omega , \end{aligned}$$

in the distributional sense, with \(V\in L^\infty (\Omega )\), where \(u\equiv 0\) on \(\partial \Omega .\) We prove a sharp inequality involving \(||V||_{L^{\infty }(\Omega )}\) and the first eigenvalue of the Laplacian on geodesic balls in simply connected spaces with constant curvature, which slightly generalises the well-known Faber–Krahn isoperimetric inequality. Moreover, in a Riemannian manifold which is not necessarily simply connected, we obtain a lower bound for \(||V||_{L^{\infty }(\Omega )}\) in terms of its isoperimetric or Cheeger constant. As an application, we show that if \(\Omega \) is a domain on a m-dimensional minimal submanifold of \({\mathbb {R}}^n\) which lies in a ball of radius R, then

$$\begin{aligned} ||V||_{L^{\infty }(\Omega )}\ge \left( \frac{m}{2R}\right) ^{2}. \end{aligned}$$

     

Classification of pinched positive scalar curvature manifolds

Let (Mn,g), n?3, be a smooth closed Riemannian manifold with positive scalar curvature Rg. There exists a positive constant C=C(M,g) defined by mean curvature of Euclidean isometric immersions, which is a geometric invariant, such that Rg?n(n−1)C. In this paper we prove that Rg=n(n−1)C if and only if (Mn,g) is isometric to the Euclidean sphere Sn(C) with constant sectional curvature C. Also, there exists a Riemannian metric g on Mn such that the scalar curvature satisfies the pinched condition

     

Amyloid fibril formation and other aggregate species formed by human serum albumin association

Under in vitro solution conditions where the native state is destabilized, many proteins present an abnormal structure and metabolism associated with a strong tendency to self-aggregation into a polymeric amyloid fibril structure, suggesting that this ability is a generic feature of the polypeptide chains. Such structures play a key role in different pathogenesis of neurodegenerative diseases such as Alzheimer, Parkinson, or Creutzfeldt-Jakob. Here, we report the formation of amyloid fibrils in the plasma protein human serum albumin under different in vitro conditions monitored using a combination of spectrophotometric and microscopic techniques. Amyloid fibril formation, therefore, is also allowed in a protein with a high degree of structural complexity. We also infer from experimental data the existence of other protein aggregated species than fibrils, some of which seem to be formed by a structural rearrangement of the proper fibrils.