Oxetanes: Recent Advances in Synthesis, Reactivity and Medicinal Chemistry

The 4-membered oxetane ring has been increasingly exploited for its behaviors, i.e. influence on physicochemical properties as a stable motif in medicinal chemistry, and propensity to undergo ring opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last 5 years up to the end of 2015. These methods are clustered by strategy for preparation of the ring (Sections 3 and 4), and further derivatisation of preformed oxetane-containing building blocks (Sections 5-7). Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally examples of oxetane derivatives in ring opening and ring expansion reactions are described

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process. Although it is well known that proteins regulate Cl-/HCO3- exchange in cells, these results suggest that small molecules may also be able to regulate the concentration of these anions in biological systems

Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment.

The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of ±5° to ±30° between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation

Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing

Risk Factors for Primary Clostridium difficile Infection; Results From the Observational Study of Risk Factors for Clostridium difficile Infection in Hospitalized Patients With Infective Diarrhea (ORCHID)

Background: There are inconsistent data on the risk factors for Clostridium difficile infection (CDI) in the literature. Aims: To use two C. difficile infection (CDI) case-control study groups to compare risk factors in hospitalized patients with diarrhea across different countries. Methods: A multi-center group of CDI cases/controls were identified by standardized testing from seven countries from the prior EUropean, multi-center, prospective bi-annual point prevalence study of CLostridium difficile Infection in hospitalized patients with Diarrhea (EUCLID). A second group of CDI cases/controls was identified from a single center in Germany [parallel study site (PSS)]. Data were extracted from the medical notes to assess CDI risk factors. Univariate analyses and multivariate logistic regression models were used to identify and compare risk factors between the two groups. Results: There were 253 and 158 cases and 921 and 584 controls in the PSS and EUCLID groups, respectively. Significant variables from univariate analyses in both groups were age ≥65, number of antibiotics (OR 1.2 for each additional antibiotic) and prior hospital admission (all p < 0.001). Congestive heart failure, diabetes, admission from assisted living or Emergency Department, proton pump inhibitors, and chronic renal disease were significant in PSS (all p < 0.05) but not EUCLID. Dementia and admitted with other bacterial diseases were significant in EUCLID (p < 0.05) but not PSS. Following multivariate analyses, age ≥ 65, number of antibiotics and prior hospital admission were consistently identified as CDI risk factors in each individual group and combined datasets. Conclusion: Our results show that the same CDI risk factors were identified across datasets. These were age ≥ 65 years, antibiotic use and prior hospital admission. Importantly, the odds of developing CDI increases with each extra antibiotic prescribed

Genome-Wide Study of Gene Variants Associated with Differential Cardiovascular Event Reduction by Pravastatin Therapy

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins

Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays.

By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein-protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range

Modelling the US Federal Spending Process: Overview and Implications

The object of study is the US Federal budget process - an institutional process of increasing prominence in US and world affairs - which is unique in generating quantitative data for scholarly research. The authors first outline their rigorous, but simple, econometric models of how budget decisions are made, coordinated, and implemented and then trace the implications of their high-inertia view of the process for the US economic cycle. They propound a presidential and Congressional ambition model of current and postwar cyclical economic difficulties, including stagflation, in terms of a macroeconomic model of the US economy in which federal governmental expenditure is endogenous. The chapter concludes with speculation on the disastrous consequences for society of the growth of a sluggishly adaptable bureaucratic process operating in a rapidly changing economic and social environment