Biotransformation of aromatic hydrocarbons and organic sulphides by fungi

Toluene is converted to benzyl alcohol by the fungi Mortierella isabellina and Helminthosporium species; in the latter case, the product is further metabolized. Toluene-a -d 1 , toluene-a,a-d2, and toluene-a,a,a-d 3 have been used with Mortierellaisabellina in a series of experiments to determine both primary and secondary deuterium kinetic isotope effects for the enzymic benzylic hydroxylation reaction. The values obtained, intermolecular primary kH/kD = intramolecular p rim a r y kH r kD = 1. 0 2 + O. 0 5, and sec 0 n dar y k H I kD = 1. 37 .:!. 0.05, suggest a mechanism for the reaction involving benzylic proton removal from a radical intermediate in a non-symmetrical transition state. 2H NMR (30.7 MHz) studies using ethylbenzene-l,1-d 2 , 3 -fluoroethylbenzene-l,1-d 2 , 4 -fluoroethylbenzene-l,1-d 2 , and toluene-dB as substrates with Mortierella isabellina suggest, based on the observable differences in rates of conversion between the substrates, that the hydroxylation of hydrocarbons at the benzylic position proceeds via a one electron abstraction from the aromatic ring, giving a radical cation. A series of 1,3-oxathiolanes (eight) were incubated with Mortierella isabellina , Helminthosporium , Rhizopus arrhizus , and Aspergillus niger . Sulphoxides were obtained from Mortierella isabellina and Rhizopus arrhizus using the substrates 2-phenyl-, 2-methyl-2-phenyl-, and 2-phenyl-2-tert. butyl-l,3-oxathiolane. The relative stereochemistry of 2-methyl-2-phenyl-l,3-oxathiolan-l-oxide was assigned based on lH decoupling, n.O.e, 1 and H NMR experiments. The lH NMR (200 MHz) of the methylene protons of 2-methyl-2-phenyl-l,3-oxathiolan-l-oxide was used as a diagnostic standard in assigning the relative stereochemistry of 2-phenyl-l,3-oxathiolan-l-oxide and 2-phenyl-2-tert. butyl-l,3-oxathiolan-l-oxide. The sulphoxides obtained were consistent with an oxidation occurring from the opposite side of the molecule to the phenyl substituent

Benzo-fused Lactams from a Diversity-oriented Synthesis (DOS) Library as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

We report a new series of 8-membered benzo-fused lactams that inhibit cellular lipid uptake from HDL particles mediated by Scavenger Receptor, Class B, Type I (SR-BI). The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR), measuring the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is part of a previously reported diversity-oriented synthesis (DOS) library prepared via a build-couple-pair approach. Detailed structure–activity relationship (SAR) studies were performed with a selection of the original library, as well as additional analogs prepared via solution phase synthesis. These studies demonstrate that the orientation of the substituents on the aliphatic ring have a critical effect on activity. Additionally, a lipophilic group is required at the western end of the molecule, and a northern hydroxyl group and a southern sulfonamide substituent also proved to be optimal. Compound 2p was found to possess a superior combination of potency (av IC50 = 0.10 μM) and solubility (79 μM in PBS), and it was designated as probe ML312

Discovery of Bisamide-heterocycles as Inhibitors of Scavenger Receptor BI (SR-BI)-mediated Lipid Uptake

A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure–activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50 = 17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278

Indolinyl-Thiazole Based Inhibitors of Scavenger Receptor-BI (SR-BI)-Mediated Lipid Transport

A potent class of indolinyl-thiazole based inhibitors of cellular lipid uptake mediated by scavenger receptor, class B, type I (SR-BI) was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) in an assay measuring the uptake of the fluorescent lipid DiI from HDL particles. This class of compounds is represented by ML278 (17–11), a potent (average IC50 = 6 nM) and reversible inhibitor of lipid uptake via SR-BI. ML278 is a plasma-stable, noncytotoxic probe that exhibits moderate metabolic stability, thus displaying improved properties for in vitro and in vivo studies. Strikingly, ML278 and previously described inhibitors of lipid transport share the property of increasing the binding of HDL to SR-BI, rather than blocking it, suggesting there may be similarities in their mechanisms of action

THERMAL ACTIVATED CARRIER TRANSFER BETWEEN InAs QUANTUM DOTS IN VERY LOW DENSITY SAMPLES

During the last decade, a great effort has been made studying the temperature evolution of QD emission, obtaining good agreements between experimental data and theoretical models. Thermal escape through wetting layer (WL) or by phonon assisted tunneling is usually claimed to describe carrier transfer in monomodal and bimodal QDs distributions. In the present study we have analyzed this phenomenon in two different samples containing a very low density of InAs/GaAs QDs, namely 16.5 and 25 QD/?m2 (Samples I and II, respectively). A detailed experimental study as a function of temperature has been carried out by using ensemble photoluminescence (PL), micro-PL and time resolved PL (TRPL) techniques. In both samples coexist two QD size distributions: (i) a small size one emitting in the region 1.25-1.35 eV (SQD family) and (ii) a large size one emitting in the region 1.05-1.20 eV (LQD family), as shown in Figs. 1.a-b. In sample I the SQD family dominates in intensity and the opposite is observed in Sample II, yet their temperature evolution is similar. An increase of the LQD integrated intensity is observed simultaneously with the decrease of the SDQ band, as observed in Figs. 1.c-d. This behavior is corroborated by the first time by Micro-PL of single QDs (see Fig. 1.e) belonging to both families detected simultaneously. The experiment is performed by using a multimode optical fiber in the detection arm of our confocal microscope and a monomode optical fiber to excite the SQD. A set of balance equations is used to reproduce the measured temperature evolution of the whole PL spectrum by introducing the transfer between SQD towards neighbor LQDs via WL states and the measured TRPL data

Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates

The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.National Institutes of Health (U.S.) (1 R03 MH086456-01

Racism: A Teenagers\u27 Perspective Results of Preliminary Research from Madrid, Spain

In mid-June, 2005, the members of the INTER Center received a collaboration proposal from FETE-UGT8, with the objective of carrying out a brief exploratory study on the perceptions and experiences that young people and adolescents, mainly immigrants, have concerning possible experiences of discrimination and racism in their immediate surroundings. The initial objectives of the project were expanded due to the dynamics of the project itself. New focuses of attention and social, educational and personal dynamics, which can condition to a certain extent the experiences that immigrant adolescents undergo, were detected. The project initially consisted of a series of interviews with adolescents between 12 and 18 years of age. A total of 20 interviews were carried out, some of them group interviews. We consider this project focus, although positive, to be limited, and we think that it would have been necessary to broaden the sample and consider other people in the young people’s social and family environment (family members, friends, classmates, professors, all of them of different origins, including the host country)

CD32 Expression is not Associated to HIV-DNA content in CD4 cell subsets of individuals with Different Levels of HIV Control

A recent study has pointed out to CD32a as a potential biomarker of HIV-persistent CD4 cells. We have characterized the level and phenotype of CD32+ cells contained in different subsets of CD4 T-cells and its potential correlation with level of total HIV-DNA in thirty HIV patients (10 typical progressors naive for cART, 10 cART-suppressed patients, and 10 elite controllers). Total HIV-DNA was quantified in different subsets of CD4 T-cells: Trm and pTfh cells. Level and immunephenotype of CD32+ cells were analyzed in these same subsets by flow cytometry. CD32 expression in Trm and pTfh subsets was similar in the different groups, and there was no significant correlation between the level of total HIV-DNA and the level of CD32 expression in these subsets. However, total HIV-DNA level was correlated with expression of CD127 (rho = -0.46, p = 0.043) and of CCR6 (rho = -0.418, p = 0.027) on CD32+ cells. Our results do not support CD32 as a biomarker of total HIV-DNA content. However, analyzing the expression of certain markers by CD32+ cells could improve the utility of this marker in the clinical setting, prompting the necessity of further studies to both validate our results and to explore the potential utility of certain markers expressed by CD32+ cells.We would like to thank all patients and healthy donors who participated in the study. This study has been funded by projects CP14/00198, PI16/01769, and RD16/0025/0013 integrated in the State Plan for Scientific and Technical Research and Innovation and co-funded by ISCIII-Sub-Directorate General for Research Assessment and Promotion and European Regional Development Fund (ERDF). N Rallon is a Miguel Servet investigator from the Spanish Carlos III Institute of Health (ISCIII), grant CP14/00198, Madrid, Spain. Maria Angeles Navarrete-Munoz was funded by RD16/0025/0013 and the Intramural Research Scholarship from IIS-FJD. Clara Restrepo was funded by project RD16/0025/0013. M Garcia is a predoctoral student co-funded by CP14/00198 project and the Intramural Research Scholarship from IIS-FJD.S