Polycondensed heterocycles. II. A new preparative route to 11-Oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine

6-Methylthio-10-oxo-5H,10H-pyrrolo[1,2-b]isoquinoline 11 was isolated in an attempted synthesis of 11-oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine 1 from 1-(2-methylthiobenzyl)pyrrole-2-carboxylic acid chloride 9 , obtained using as starting material o-methylthiobenzyl bromide 3 and passing through 1-(2-methylthiobenzyl)pyrrole-2-carbonitrile 5 , by cyclization with aluminum chloride. However the successful demethylation with sodium in dimethylacetamide of 1-(2-methylthiobenzyl)pyrrole-2-carboxyamide 12 , formed by hydrolysis of nitrile 5 , allowed us to prepare by another way the corresponding thiol 13 and consequently the 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 14 , which when subjected to intramolecular ring closure by CDI in place of DCC gave 1 in higher yield, 69% instead of 43%. Finally, the direct cyanation of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 16 , prepared utilizing the 1-(2-mercaptobenzyl)pyrrole 15 obtained by demethylation of the corresponding thioanisol 4 which was carried out as above, afforded the unexpected 1-(2-ethylthio-benzyl)pyrrole-2-carbonitrile 17 .     

Strong Unique Continuation Properties of Generalized Baouendi–Grushin Operators

This paper gives a quantitative control of the order of zero of a weak solution to perturbations of the Baouendi–Grushin operator, which generalizes the result due to Aronszaijn, Krzywicki, and Szarski valid for elliptic operators in divergence form with Lipschitz continuous coefficients.     

Neutral loss analysis of amino acids by desorption electrospray ionization using an unmodified tandem quadrupole mass spectrometer

A new method to analyze free amino acids using desorption electrospray ionization (DESI) has been implemented. The method is based on the neutral loss mode determination of underivatized amino acids using a tandem quadrupole mass spectrometer equipped with an unmodified atmospheric interface. Qualitative and quantitative optimization of DESI parameters, including ESI voltage, solvent flow rate, angle of collection and incidence, gas flow and temperatures, was performed for amino acids detection. The parameters for DESI analysis were evaluated using a mixture of valine, leucine, methionine, phenylalanine and tyrosine standards. A few microliters of this mixture were deposited on a slide, dried and analyzed at a flow rate of 2 microL/min. The optimal ionization response was obtained using laboratory glass slides and an equivalent solution of water/methanol doped with 2% of formic acid. The method specificity was evaluated by comparing product ion spectra and neutral loss analysis of amino acids obtained either by DESI or by electrospray ionization flow injection analysis (ESI-FIA). To evaluate the quantitative response on amino acids analyzed by DESI, calibration curves were performed on amino acid standard solutions spiked with a fixed amount of labelled amino acids. The method was also employed to analyze free amino acids from blood spots, after a rapid solvent extraction without other sample pretreatment, from positive and negative subjects. The method enables one to analyze biological samples and to discriminate healthy subjects from patients affected by inherited metabolic diseases. The intrinsic high-throughput analysis of DESI represents an opportunity, because of its potential application in clinical chemistry, for the expanded screening of some inborn errors of metabolism.     

Perelman’s Entropy and Doubling Property on Riemannian Manifolds

The purpose of this work is to study some monotone functionals of the heat kernel on a complete Riemannian manifold with nonnegative Ricci curvature. In particular, we show that on these manifolds, the gradient estimate of Li and Yau (Acta Math. 156, 153–201, 1986), the gradient estimate of Ni (J. Geom. Anal. 14(1), 87–100, 2004), the monotonicity of the Perelman’s entropy and the volume doubling property are all consequences of an entropy inequality recently discovered by Baudoin and Garofalo, , 2009. The latter is a linearized version of a logarithmic Sobolev inequality that is due to D. Bakry and M. Ledoux (Rev. Mat. Iberoam. 22, 683–702, 2006).     

Toward Multitasking Pharmacological COX-Targeting Agents: Non-Steroidal Anti-Inflammatory Prodrugs with Antiproliferative Effects

The antitumor activity of certain anti-inflammatory drugs is often attributed to an indirect effect based on the inhibition of COX enzymes. In the case of anti-inflammatory prodrugs, this property could be attributed to the parent molecules with mechanism other than COX inhibition, particularly through formulations capable of slowing down their metabolic conversion. In this work, a pilot docking study aimed at comparing the interaction of two prodrugs, nabumetone (NB) and its tricyclic analog 7-methoxy-2,3-dihydro-1H-cyclopenta[b]naphthalen-1-one (MC), and their common active metabolite 6-methoxy-2-naphthylacetic acid (MNA) with the COX binding site, was carried out. Cytotoxicity, cytofluorimetry, and protein expression assays on prodrugs were also performed to assess their potential as antiproliferative agents that could help hypothesize an effective use as anticancer therapeutics. Encouraging results suggest that the studied compounds could act not only as precursors of the anti-inflammatory metabolite, but also as direct antiproliferative agents.     

Some new monotonicity formulas and the singular set in the lower dimensional obstacle problem

We construct two new one-parameter families of monotonicity formulas to study the free boundary points in the lower dimensional obstacle problem. The first one is a family of Weiss type formulas geared for points of any given homogeneity and the second one is a family of Monneau type formulas suited for the study of singular points. We show the uniqueness and continuous dependence of the blowups at singular points of given homogeneity. This allows to prove a structural theorem for the singular set. Our approach works both for zero and smooth non-zero lower dimensional obstacles. The study in the latter case is based on a generalization of Almgren’s frequency formula, first established by Caffarelli, Salsa, and Silvestre. N. Garofalo is supported in part by NSF grant DMS-0701001. A. Petrosyan is supported in part by NSF grant DMS-0701015.