Characterization of particulate-bound PAHs in rural households using different types of domestic energy in Henan Province, China.

The concentrations and composition of sixteen PAHs adsorbed to respirable particulate matter (PM10≤10 μm) and inhalable particulate matter (PM2.5≤2.5 μm) were determined during autumn and winter in rural households of Henan Province, China, which used four types of domestic energy [crop residues, coal, liquid petroleum gas (LPG) and electricity] for cooking and heating.

Potential cytotoxicity of water-soluble fraction of dust and particulate matters and relation to metal(loid)s based on three human cell lines.

Hepatocellular liver carcinoma (HepG2), human skin derived keratinocyte (KERTr,) and lung epithelial carcinoma (A549) were employed in MTT assay to evaluate the cytotoxicity of water-soluble fraction of road dust, air-conditioning (AC) filter dust and PM2.5 via ingestion, dermal contact and inhalation. Their effects on cell growth were dependent on exposure time and concentration.

Levels of PM2.5/PM10 and associated metal(loid)s in rural households of Henan Province, China.

Although a majority of China's rural residents use solid fuels (biomass and coal) for household cooking and heating, clean energy such as electricity and liquid petroleum gas is becoming more popular in the rural area. Unfortunately, both solid fuels and clean energy could result in indoor air pollution. Daily respirable particulate matter (PM≤10 μm) and inhalable particulate matter (PM≤2.

Contamination and risk assessment (based on bioaccessibility via ingestion and inhalation) of metal(loid)s in outdoor and indoor particles from urban centers of Guangzhou, China.

Road dust, household air-conditioning (AC) filter dust and PM2.5 were collected to investigate the contamination of metal(loid)s (Cr, Mn, Ni, Cu, Zn, As, Cd, Sn, Sb, Hg and Pb) in outdoor and indoor urban environments of Guangzhou. Zinc was found to be the most abundant element in road dust and household PM2.

Mercury levels in road dust and household TSP/PM₂.₅ related to concentrations in hair in Guangzhou, China.

Road dust, household total suspended particulate matters (TSP) and PM₂.₅ were collected in urban area of Guangzhou, south of China, to investigate the concentrations of total mercury (THg) and methyl mercury (MeHg). The household PM₂.

Stable carbon isotope ratio analysis of anhydrosugars in biomass burning aerosol particles from source samples.

A new method for stable carbon isotope ratio analysis of anhydrosugars from biomass burning aerosol particle source filter samples was developed by employing Thermal Desorption--2 Dimensional Gas Chromatography--Isotope Ratio Mass Spectrometry (TD-2DGC-IRMS). Compound specific isotopic measurements of levoglucosan, mannosan, and galactosan performed by TD-2DGC-IRMS in a standard mixture show good agreement with isotopic measurements of the bulk anhydrosugars, carried out by Elemental Analyzer--Isotope Ratio Mass Spectrometry (EA-IRMS). The established method was applied to determine the isotope ratios of levoglucosan, mannosan, and galactosan from source samples collected during combustion of hard wood, softwood, and crop residues.

The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs.

The discovery and evaluation of potent and long-acting oral sulfonamidopyrrolidin-2-one factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs are described. Unexpected selectivity issues versus tissue plasminogen activator in the former series were addressed in the later, delivering a robust candidate for progression towards clinical studies.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.

The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.

Antithrombotic potential of GW813893: a novel, orally active, active-site directed factor Xa inhibitor.

Background: Factor Xa (FXa) has been a target of considerable interest for drug development efforts aimed at suppressing thrombosis. In this report, a new orally active, small molecule, active-site directed FXa inhibitor, GW813893, has been profiled in a succession of in vitro and in vivo assays involved in its preclinical characterization as a potential antithrombotic therapeutic.

Methods: In vitro profiling of GW813893 consisted of assessing its inhibitory potential against FXa and a broad panel of related and unrelated enzymes and receptors.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.

Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Selective and dual action orally active inhibitors of thrombin and factor Xa.

The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.

Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors.

Sulfonamide-related conformational effects and their importance in structure-based design.

Structure-based design (SBD) is a challenging endeavour since even localised SAR can hardly ever be explained by the variation of just one dominating factor. Here, we present a rare example where structural information combined with ab initio calculations clearly indicate that the observed difference in biological activity is dominated by conformational effects. The learnings discussed are successfully put to the test and have the potential to be of general use as a qualitative guide in SBD efforts.

Arylsulfonamides: a study of the relationship between activity and conformational preferences for a series of factor Xa inhibitors.

Torsional scans of sulfonamide S-C bonds in small model systems of a series of arylsulfonamide factor Xa inhibitors were performed in order to investigate if conformational effects can help to rationalise the observed SAR. Computational results were in good agreement with the experimental data indicating that the sulfonamide conformation plays an important role in determining the activity in this particular series of factor Xa inhibitors.

Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.

Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.

A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.

Mechanistic insight into the lanthanide(III) salt catalysed monoacylation of symmetrical diols from structural models.

Model studies are presented that suggest the mechanism of the lanthanide(III) salt catalysed mono acylation of symmetrical diols proceeds via chelation of the diol and the anhydride to the lanthanide salt, followed by an 'intramolecular' acyl transfer.

A one-step procedure for the monoacylation of symmetrical 1,2-diols.

A series of lanthanide (III) salts have been shown to catalyze the monoacylation of symmetrical 1,2-diols by carboxylic acid anhydrides with surprisingly high selectivity.