Search

The natural product quinine has been known to humankind for centuries, and in that time has played a pivotal role in the treatment of malaria. Quinine, and the related cinchona alkaloids, have seen widespread contemporary use across chemical and biological disciplines, owing in part to the plethora of functional groups and stereochemical information contained within their scaffold. This review focuses on site‐selective synthetic modifications of the cinchona alkaloids. Our comparative analysis may act as a 'user manual' for the selective functionalisation of the cinchona alkaloids, and aims to promote consideration of remarkable and lesser‐understood aspects of cinchona chemistry. [ABSTRACT FROM AUTHOR]

Directed Pd‐catalysed β‐(hetero)arylation of the 7‐oxabicyclo[2.2.1]heptane framework is described. Arylated products were formed in up to 99 % yield, and heteroarylated products in up to 88 % yield with complete diastereoselectivity. Different minor diarylated side products were formed, depending on whether electron deficient aryl or pyridyl iodides were used as the coupling partners. Cleavage of the 8‐aminoquinoline directing group provided small bridged compounds that may be of value in fragment based drug discovery. [ABSTRACT FROM AUTHOR]

The pseudo‐natural product (pseudo‐NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three‐dimensional pseudo‐NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B. [ABSTRACT FROM AUTHOR]

We describe the efficient synthesis of novel dehydroxyquinines by arylation of quincorine bromide using Ni‐catalysed cross electrophile coupling. The method demonstrates robust compatibility with (hetero)aryl bromides bearing diverse functional groups. Oxidation at C‐9 of the dehydroxyquinines expediently provided quinine‐inspired pseudo‐natural products ('quinalogs'). Investigation of the compound collection against Plasmodium falciparum revealed a new insight into the structure activity relationship of quinine. Analogs bearing specifically functionalised pyridines, in place of the 6‐methoxyquinoline ring of quinine, retained activity at the same order of magnitude, albeit not exceeding the activity of the natural product. This synthetic strategy conveniently enables iteration of the aromatic component of quinine for the first time, and holds promise for the development of effective new antimalarials. [ABSTRACT FROM AUTHOR]

Aplastic anemia (AA) is a rare bone marrow failure disorder that is treated with either allogeneic stem cell transplant or immunosuppressive therapy (IST) consisting of antithymocyte globulin (ATG), cyclosporine (CSA), and eltrombopag. While outcomes are favorable in younger patients, older patients (>60) have significantly worse long‐term survival. The dose of ATG is often reduced in older patients and those with multiple comorbidities given concerns for tolerability. The efficacy and safety of dose‐attenuated IST in this population is largely undescribed. We performed a retrospective review of patients with AA treated with IST. Our analysis was confounded by changes in practice patterns and the introduction of eltrombopag. We identified 53 patients >60 years old, of which, 20 received dose‐attenuated IST, with no statistically significant difference in overall survival between full and attenuated dose cohorts. Overall response rates in both cohorts were similar at 6 months at 71% and 68%. There were more documented infectious complications in the full dose cohort (13 vs. 3). This supports the consideration of dose‐attenuated IST in older patients with concerns about tolerance of IST. Lastly, our data confirmed favorable outcomes of younger patients receiving IST, especially in combination with eltrombopag. [ABSTRACT FROM AUTHOR]

Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure. [ABSTRACT FROM AUTHOR]

Pseudo‐natural‐product (NP) design combines natural product fragments to provide unprecedented NP‐inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo‐NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell‐based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd‐catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole‐containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole‐1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation‐ and rapamycin‐induced autophagy by targeting the lipid kinase VPS34. [ABSTRACT FROM AUTHOR]

Chemical proteomics is widely applied in small‐molecule target identification. However, in general it does not identify non‐protein small‐molecule targets, and thus, alternative methods for target identification are in high demand. We report the discovery of the autophagy inhibitor autoquin and the identification of its molecular mode of action using image‐based morphological profiling in the cell painting assay. A compound‐induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. In addition, autoquin sequesters Fe2+ in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. Such a mechanism of action would have been challenging to unravel by current methods. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules, warranting wider application in chemical biology. [ABSTRACT FROM AUTHOR]

Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape‐diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3‐rich molecular scaffolds. The resulting set of 80 fragments was highly three‐dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high‐throughput protein crystallography against Aurora‐A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape‐diverse screening collections to be more fully assessed. [ABSTRACT FROM AUTHOR]

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A 'top-down' synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3-rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space. [ABSTRACT FROM AUTHOR]

Mit der Verbesserung unserer Kenntnisse zur Bedeutung bestimmter Moleküleigenschaften bei Anwendungen im Rahmen der Wirkstoffsuche wird das Ausmaß immer klarer, in dem veröffentlichte Synthesemethoden erwünschten Kriterien genügen (oder nicht genügen). Wir beschreiben hier, wie die Anwendung einfacher (und in vielen Fällen frei verfügbarer) Rechenprogramme genutzt werden kann, um ein semiquantitatives Verständnis des Potenzials von neuen Methoden in der Wirkstoff ‐ Forschung zu entwickeln. Diese Analyse kann sich unter anderem auf die Planung verbesserter Studien zum Substratspektrum auswirken, die Priorisierung von bestimmten Beispielstrukturen für die Synthese leiten und Ansprüche für potenzielle künftige Anwendungen von neuen Methoden begründen. Die Eigenschaftsleiter: Die sorgfältige Kontrolle von Moleküleigenschaften ist eng mit dem Erfolg bei der Suche nach niedermolekularen Leitstrukturen verknüpft. Computerprogramme zur Berechnung solcher Eigenschaften sind inzwischen allgemein verfügbar, viele davon als Freeware. Mithilfe dieser Programme kann die Anwendung neuer Synthesemethoden gesteuert und die Anpassung an die Anforderungen künftiger Wirkstoffsuchen bewertet werden. [ABSTRACT FROM AUTHOR]

As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 68-year-old male presented with haematemesis to the ED of a regional hospital via ambulance. Topics include the patient has intubated prior to gaining access to the right femoral artery using a 7-Fr introducer arterial sheath; and the traditional technique to stem uncontrollable below-diaphragm bleeding has been resuscitative thoracotomy.

OBJECTIVES: To assess the longitudinal association between sleep disturbances (insomnia and daytime sleepiness) and incidence of dementia and cognitive decline in older men. DESIGN: Community-based longitudinal cohort study. SETTING: The Honolulu-Asia Aging Study of dementia that is linked to the Honolulu Heart Program's fourth examination, conducted 1991–1993, and the 3-year follow-up fifth examination, conducted 1994–1996. PARTICIPANTS: Two thousand three hundred forty-six Japanese-American men age 71 to 93 years who screened negative for prevalent dementia at baseline and were screened again for dementia incidence in a 3-year follow-up examination. MEASUREMENTS: Baseline self-reports of trouble falling asleep or early morning awakening (insomnia) and being sleepy during the day (daytime sleepiness); Cognitive Abilities Screening Instrument (CASI) scores from baseline and followup; clinical diagnosis of incident dementia; and other baseline measures including age, years of education, body mass index, depressive symptoms, and history of hypertension, heart disease, diabetes mellitus, asthma, and use of benzodiazepines. RESULTS: After adjusting for age and other factors, persons reporting excessive daytime sleepiness at baseline (8%) were twice as likely to be diagnosed with incident dementia than were those not reporting daytime sleepiness (odds ratio (OR) = 2.19, 95% confidence interval (CI) = 1.37–3.50) and about 40% more likely to have ≥9 point drop in their CASI score between examinations (OR = 1.44, 95% CI = 1.01–2.08). In contrast, insomnia was not associated with cognitive decline or incidence of dementia. CONCLUSIONS: Daytime sleepiness in older adults may be an early indicator of decline in cognitive functioning and onset of dementia. [ABSTRACT FROM AUTHOR]

Examines the impact of insomnia on cognitive functioning of older adults in the U.S. Influence of symptoms of insomnia on the increase risk of cognitive decline in aging; Interaction between sleep complaints and depressed mood; Complication of chronic sleep problems.

The article presents a case study of a young woman who was diagnosed with diaphragmatic hernia of Bochdalek. The patient presented with abdominal pain, nausea and vomiting and tests found absent breath sounds throughout the left part of her chest. She underwent caesarean section and delivered a healthy baby girl.

Review: [33 refs. [ABSTRACT FROM AUTHOR]

Four amino acid-derived building blocks are converted into 22 scaffolds, e.g. azides (III) and (XIV), hydantoins (IV), lactams (VI), tetrahydropyridines (IX), and azepanes (XII). [ABSTRACT FROM AUTHOR]

S-Alkenyl-N-arylthiocarbamates undergo carbolithiation with a range of organolithium reagents, generating benzyllithium intermediates in a stereospecific manner which may undergo N to C aryl migration to yield thiocarbamates with tertiary substituents. [ABSTRACT FROM AUTHOR]

Replies to a critique of the authors' study 'The impact of insomnia on cognitive functioning in older adults,' published in the 'Journal of the American Geriatric Society,' 2001;49 issue. Pharmacological interventions; Attenuating sleep complaints of the elderly; Insomnia-like symptoms.