Rational design, synthesis and pharmacological characterization of novel aminopeptidase A inhibitors.

Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor.

Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for Mouse Studies.

Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket.

Contamination of water, soil, and plants by micropollutants from reclaimed wastewater and sludge from a wastewater treatment plant.

Several studies have shown that plants can absorb various micropollutants. The behavior of micropollutants from wastewater treatment plant resources was comprehensively investigated in raised beds in which either a mixture of vegetables or maize was grown. The beds were either irrigated with treated wastewater or enriched with sewage sludge or composted sewage sludge.

Dissipation of twelve organic micropollutants in three different soils: Effect of soil characteristics and microbial composition.

The dissipation kinetics and half-lives of selected organic micropollutants, including pharmaceuticals and others, were systematically investigated and compared among different soil types. While some pollutants (e.g.

Selective accumulation of pharmaceutical residues from 6 different soils by plants: a comparative study on onion, radish, and spinach.

The accumulation of six pharmaceuticals of different therapeutic uses has been thoroughly investigated and compared between onion, spinach, and radish plants grown in six soil types. While neutral molecules (e.g.

A novel multiscale biophysical model to predict the fate of ionizable compounds in the soil-plant continuum.

Soil pollution from emerging contaminants poses a significant threat to water resources management and food production. The development of numerical models to describe the reactive transport of chemicals in both soil and plant is of paramount importance to elaborate mitigation strategies. To this aim, in the present study, a multiscale biophysical model is developed to predict the fate of ionizable compound in the soil-plant continuum.

On the Use of Mechanistic Soil-Plant Uptake Models: A Comprehensive Experimental and Numerical Analysis on the Translocation of Carbamazepine in Green Pea Plants.

Food contamination is a major worldwide risk for human health. Dynamic plant uptake of pollutants from contaminated environments is the preferred pathway into the human and animal food chain. Mechanistic models represent a fundamental tool for risk assessment and the development of mitigation strategies.

How microbial community composition, sorption and simultaneous application of six pharmaceuticals affect their dissipation in soils.

Pharmaceuticals may enter soils due to the application of treated wastewater or biosolids. Their leakage from soils towards the groundwater, and their uptake by plants is largely controlled by sorption and degradation of those compounds in soils. Standard laboratory batch degradation and sorption experiments were performed using soil samples obtained from the top horizons of seven different soil types and 6 pharmaceuticals (carbamazepine, irbesartan, fexofenadine, clindamycin and sulfamethoxazole), which were applied either as single-solute solutions or as mixtures (not for sorption).

Competitive and synergic sorption of carbamazepine, citalopram, clindamycin, fexofenadine, irbesartan and sulfamethoxazole in seven soils.

Sorption of pharmaceuticals, which can occur in soils, may differ when present in a soil solution as a single compound or in a solution with other pharmaceuticals. Therefore, the sorption isotherms described by the Freundlich equations were evaluated for 6 compounds, which were applied in solutions of a single pharmaceutical, two pharmaceuticals or all pharmaceuticals to seven soils. Study mainly focused on a behavior of fexofenadine and irbesartan that occurred in soils in 3 forms (cationic, zwitter-ionic or neutral, anionic).

Soil influences on uptake and transfer of pharmaceuticals from sewage sludge amended soils to spinach.

Sewage sludge from wastewater treatment plants, which may contain various contaminants including pharmaceuticals, is often used as a soil amendment. These contaminants may subsequently be taken up by plants. In the present study we examined uptake of select pharmaceuticals from sewage sludge applied to soils by spinach plants.

Root uptake of atenolol, sulfamethoxazole and carbamazepine, and their transformation in three soils and four plants.

Soils can be contaminated by pharmaceuticals. The aim of this study was to evaluate the impact of soil conditions (influencing sorption and persistence of pharmaceuticals in soils) and plant type on the root uptake of selected pharmaceuticals and their transformation in plant-soil systems. Four plants (lamb's lettuce, spinach, arugula, radish) planted in 3 soils were irrigated for 20 days (26) with water contaminated by one of 3 pharmaceuticals (carbamazepine, atenolol, sulfamethoxazole) or their mixture.

Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.

Objective: Our goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose.

Methods: In this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1-3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m weekly for 3 out of 4 weeks.

Stereoselectivity Switch in the Trapping of Polar Organometallics with Andersen's Reagent-Access to Highly Stereoenriched Transformable Biphenyls.

The trapping of racemic polar carbometallic species with (-)-menthyl ( S)- p-toluenesulfinate (Andersen's reagent) typically proceeds with a very low level of resolution. In this paper, we describe a strategy that allows access to highly atropo-enriched and functionalizable biphenyls by means of Andersen's reagent under kinetic resolution conditions. In particular, useful enantiopure 2-iodobiphenyls could be obtained and were employed in a challenging hypervalent iodine-catalyzed oxidation reaction.

Bacterial Transferase MraY, a Source of Inspiration towards New Antibiotics.

The bacterial resistance to antibiotics constitutes more than ever a severe public health problem. The enzymes involved in bacterial peptidoglycan biosynthesis are pertinent targets for developing new antibiotics, notably the MraY transferase that is not targeted by any marketed drug. Many research groups are currently working on the study or the inhibition of this enzyme.

Sorption of citalopram, irbesartan and fexofenadine in soils: Estimation of sorption coefficients from soil properties.

The sorption of 3 pharmaceuticals, which may exist in 4 different forms depending on the solution pH (irbesartan in cationic, neutral and anionic, fexofenadine in cationic, zwitter-ionic and anionic, and citalopram cationic and neutral), in seven different soils was studied. The measured sorption isotherms were described by Freundlich equations, and the sorption coefficients, K (for the fixed n exponent for each compound), were related to the soil properties to derive relationships for estimating the sorption coefficients from the soil properties (i.e.

Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5'-alkynylation.

The 5'-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2',3'-di--protecting groups (R): -alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5'-isomer, whereas -silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5'-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.

Antibiotics degradation in soil: A case of clindamycin, trimethoprim, sulfamethoxazole and their transformation products.

Twelve different soil types that represent the soil compartments of the Czech Republic were fortified with three antibiotics (clindamycin (CLI), sulfamethoxazole (SUL), and trimethoprim (TRI)) to investigate their fate. Five metabolites (clindamycin sulfoxide (CSO), hydroxy clindamycin sulfoxide (HCSO), S-(SDC) and N-demethyl clindamycin (NDC), N-acetyl sulfamethoxazole (NAS), and hydroxy trimethoprim (HTR)) were detected and identified using HPLC/HRMS and HRPS in the soil matrix in this study. The identities of CSO and NAS were confirmed using commercially available reference standards.

Simultaneous sorption of four ionizable pharmaceuticals in different horizons of three soil types.

Soils may be contaminated by human or veterinary pharmaceuticals. Their behaviour in soil environment is largely controlled by sorption of different compounds in a soil solution onto soil constituents. Here we studied the sorption affinities of 4 pharmaceuticals (atenolol, trimethoprim, carbamazepine and sulfamethoxazole) applied in solute mixtures to soils taken from different horizons of 3 soil types (Greyic Phaeozem on loess, Haplic Luvisol on loess and Haplic Cambisol on gneiss).

5'-Methylene-triazole-substituted-aminoribosyl uridines as MraY inhibitors: synthesis, biological evaluation and molecular modeling.

The straightforward synthesis of 5'-methylene-[1,4]-triazole-substituted aminoribosyl uridines is described. Two families of compounds were synthesized from a unique epoxide which was regioselectively opened by acetylide ions (for compounds II) or azide ions (for compounds III). Sequential diastereoselective glycosylation with a ribosyl fluoride derivative, Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) with various complementary azide and alkyne partners afforded the targeted compounds after final deprotection.

Pharmaceuticals' sorptions relative to properties of thirteen different soils.

Transport of human and veterinary pharmaceuticals in soils and consequent ground-water contamination are influenced by many factors, including compound sorption on soil particles. Here we evaluate the sorption isotherms for 7 pharmaceuticals on 13 soils, described by Freundlich equations, and assess the impact of soil properties on various pharmaceuticals' sorption on soils. Sorption of ionizable pharmaceuticals was, in many cases, highly affected by soil pH.

Earthworm responses to different reclamation processes in post opencast mining lands during succession.

This study provides earthworm population data obtained from localities with a substantial anthropogenic impact spoils. The spoil heaps were reclaimed at the end of an opencast brown coal mining period. We studied spoils reclaimed by the two most commonly used reclamation processes: forestry and agricultural.

A diastereoselective synthesis of 5'-substituted-uridine derivatives.

A straightforward strategy for the synthesis of 5'-substituted-uridine derivatives is described. It relies on the introduction of various substituents at C-5' at the last step of the synthesis by regioselective nucleophilic opening of a unique epoxide that provides access to a small library of compounds. This epoxide results from the diastereoselective epoxidation, performed at a multigram scale, of a uridine-derived alkene.

Toward analogues of MraY natural inhibitors: synthesis of 5'-triazole-substituted-aminoribosyl uridines through a Cu-catalyzed azide-alkyne cycloaddition.

A straightforward strategy for the synthesis of triazole-containing MraY inhibitors has been developed. It involves the sequential introduction of a terminal alkyne at the 5' position of an uridine derivative and O-glycosylation with a protected aminoribose leading to an elaborated alkyne scaffold. An efficient Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) allowed the introduction of chemical diversity toward a small library of inhibitors.