Alan M. Jones

Estimation of the Contributions of Brake Dust, Tire Wear, and Resuspension to Nonexhaust Traffic Particles Derived from Atmospheric Measurements

Size-fractionated samples of airborne particulate matter have been collected in a number of campaigns at Marylebone Road, London and simultaneously at background sites either in Regents Park or at North Kensington. Analysis of these samples has enabled size distributions of total mass and of a number of elements to be determined, and roadside increments attributable to nonexhaust emissions arising from traffic activity have been calculated. Taking a novel approach, the combined use of size distribution information and tracer elements has allowed the separate estimation of the contributions of brake dust, tire dust, and resuspension to particle mass in the range 0.9-11.5 μm aerodynamic diameter and mean contributions (± s.e.) at the Marylebone Road sampling site are estimated as resuspended dust 38.1 ± 9.7%, brake dust 55.3 ± 7.0%, and tire dust 10.7 ± 2.3%, (accounting for a total of 104.1% of coarse particle mass in the traffic increment above background).

Meteorology, air quality, and health in London: The ClearfLo project

AbstractAir quality and heat are strong health drivers, and their accurate assessment and forecast are important in densely populated urban areas. However, the sources and processes leading to high concentrations of main pollutants, such as ozone, nitrogen dioxide, and fine and coarse particulate matter, in complex urban areas are not fully understood, limiting our ability to forecast air quality accurately. This paper introduces the Clean Air for London (ClearfLo; www.clearflo.ac.uk) project’s interdisciplinary approach to investigate the processes leading to poor air quality and elevated temperatures.Within ClearfLo, a large multi-institutional project funded by the U.K. Natural Environment Research Council (NERC), integrated measurements of meteorology and gaseous, and particulate composition/loading within the atmosphere of London, United Kingdom, were undertaken to understand the processes underlying poor air quality. Long-term measurement infrastructure installed at multiple levels (street and eleva...

Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies

Introduction: Checkpoint kinase (CHK) inhibitors offer the promise of enhancing the effectiveness of widely prescribed cancer chemotherapies and radiotherapy by inhibiting the DNA damage response, as well as the potential for single agent efficacy. Areas covered: This article surveys structural insights into the checkpoint kinases CHK1 and CHK2 that have been exploited to enhance the selectivity and potency of small molecule inhibitors. Furthermore, the authors review the use of mechanistic cellular assays to guide the optimisation of inhibitors. Finally, the authors discuss the status of the current clinical candidates and emerging new clinical contexts for CHK1 and CHK2 inhibitors, including the prospects for single agent efficacy. Expert opinion: Protein-bound water molecules play key roles in structural features that can be targeted to gain high selectivity for either enzyme. The results of early phase clinical trials of checkpoint inhibitors have been mixed, but significant progress has been made in testing the combination of CHK1 inhibitors with genotoxic chemotherapy. Second-generation CHK1 inhibitors are likely to benefit from increased selectivity and oral bioavailability. While the optimum therapeutic context for CHK2 inhibition remains unclear, the emergence of single agent preclinical efficacy for CHK1 inhibitors in specific tumour types exhibiting constitutive replication stress represents exciting progress in exploring the therapeutic potential of these agents.

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

Summary N-acyliminium ions are useful reactive synthetic intermediates in a variety of important carbon–carbon bond forming and cyclisation strategies in organic chemistry. The advent of an electrochemical anodic oxidation of unfunctionalised amides, more commonly known as the Shono oxidation, has provided a complementary route to the C–H activation of low reactivity intermediates. In this article, containing over 100 references, we highlight the development of the Shono-type oxidations from the original direct electrolysis methods, to the use of electroauxiliaries before arriving at indirect electrolysis methodologies. We also highlight new technologies and techniques applied to this area of electrosynthesis. We conclude with the use of this electrosynthetic approach to challenging syntheses of natural products and other complex structures for biological evaluation discussing recent technological developments in electroorganic techniques and future directions.

A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling

BACKGROUND Glycomimetics are a diverse array of saccharide-inspired compounds, designed to mimic the bioactive functions of glycosaminoglycans. Therefore, glycomimetics represent a unique source of novel therapies to target aberrant signaling and protein interactions in a wide range of diseases. We investigated the protective effects of four newly synthesized small molecule glycomimetics against lipid-induced endothelial dysfunction, with an emphasis on nitric oxide (NO) and oxidative stress. METHODS Four aromatic sugar mimetics were synthesized by the stepwise transformation of 2,5-dihydroxybenzoic acid to derivatives (C1-C4) incorporating sulfate groups to mimic the structure of heparan sulfate. RESULTS Glycomimetic-treated human umbilical vein endothelial cells (HUVECs) were exposed to palmitic acid to model lipid-induced oxidative stress. Palmitate-induced impairment of NO production was restored by the glycomimetics, through activation of Akt/eNOS signaling. Furthermore, C1-C4 significantly inhibited palmitate-induced reactive oxygen species (ROS) production, lipid peroxidation, and activity and expression of NADPH oxidase. These effects were attributed to activation of the Nrf2/ARE pathway and downstream activation of cellular antioxidant and cytoprotective proteins. In ex vivo vascular reactivity studies, the glycomimetics (C1-C4) also demonstrated a significant improvement in endothelium-dependent relaxation and decreased ROS production and NADPH oxidase activity in isolated mouse thoracic aortic rings exposed to palmitate. CONCLUSIONS The small molecule glycomimetics, C1-C4, protect against lipid-induced endothelial dysfunction through up-regulation of Akt/eNOS and Nrf2/ARE signaling pathways. Thus, carbohydrate-derived therapeutics are a new class of glycomimetic drugs targeting endothelial dysfunction, regarded as the first line of defense against vascular complications in cardiovascular disease.

Diversity-oriented synthetic strategies applied to cancer chemical biology and drug discovery

How can diversity-oriented strategies for chemical synthesis provide chemical tools to help shape our understanding of complex cancer pathways and progress anti-cancer drug discovery efforts? This review (surveying the literature from 2003 to the present) considers the applications of diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS) and associated strategies to cancer biology and drug discovery, summarising the syntheses of novel and often highly complex scaffolds from pluripotent or synthetically versatile building blocks. We highlight the role of diversity-oriented synthetic strategies in producing new chemical tools to interrogate cancer biology pathways through the assembly of relevant libraries and their application to phenotypic and biochemical screens. The use of diversity-oriented strategies to explore structure-activity relationships in more advanced drug discovery projects is discussed. We show how considering appropriate and variable focus in library design has provided a spectrum of DOS approaches relevant at all stages in anti-cancer drug discovery.

Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.

HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.

Triglycerides and Cardiovascular Risk

Accumulation of cholesterol-rich lipoproteins, notably low-density lipoprotein (LDL) cholesterol, in the subendothelial matrix of the artery wall is a key pathological process in atherosclerosis. There is overwhelming evidence that lowering plasma LDL cholesterol concentrations with statins reduces future cardiovascular events, and the effect is proportional to the degree by which LDL cholesterol concentration is lowered.1 Guidelines recommend aggressive LDL reduction in the secondary prevention of coronary artery disease (CAD),2 but, despite this and the control of other well-established risk factors, such patients, particularly after an acute coronary syndrome (ACS), remain at substantial residual risk of further events.3 In patients treated with statins, the risk of recurrent events increases in proportion to the number of components of the metabolic syndrome that they exhibit.4 Clearly other factors, including other lipoprotein abnormalities that are not significantly affected by statins, are of importance in promoting atherosclerosis. Other than LDL, the major lipoprotein classes in fasting plasma are high-density lipoprotein (HDL) and very LDL (VLDL), together with VLDL remnants formed by intravascular lipolysis of their constituent triglycerides. The fasting plasma triglyceride concentration is a surrogate marker for VLDLs and their remnants; these triglyceride-rich lipoproteins (TRLs) may be atherogenic, being sufficiently small to deliver cholesterol to the subendothelial matrix.5 The pathogenetic role of TRLs in atherogenesis is complicated by the inverse relationship that normally exists between the plasma concentrations of triglyceride and HDL cholesterol.6 Since cholesterol ester is transferred from HDL to VLDL, a process catalysed by cholesterol ester transfer protein, higher levels of VLDL promote this transfer, acting as a large sump for cholesterol ester, and so lead to lower HDL cholesterol concentrations. HDL has a number of properties that protect against cardiovascular disease (CVD), and HDL is well established …

Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1.

A naphthoquinone inhibitor of human arylamine N-acetyltransferase 1 (hNAT1), a potential cancer biomarker and therapeutic target, has been reported which undergoes a distinctive concomitant color change from red to blue upon binding to the enzyme. Here we describe the use of in silico modeling alongside structure-activity relationship studies to advance the hit compound towards a potential probe to quantify hNAT1 levels in tissues. Derivatives with both a fifty-fold higher potency against hNAT1 and a two-fold greater absorption coefficient compared to the initial hit have been synthesized; these compounds retain specificity for hNAT1 and its murine homologue mNat2 over the isoenzyme hNAT2. A relationship between pKa, inhibitor potency and colorimetric properties has also been uncovered. The high potency of representative examples against hNAT1 in ZR-75-1 cell extracts also paves the way for the development of inhibitors with improved intrinsic sensitivity which could enable detection of hNAT1 in tissue samples and potentially act as tools for elucidating the unknown role hNAT1 plays in ER+ breast cancer; this could in turn lead to a therapeutic use for such inhibitors.

Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.