Calculable physicochemical descriptors are a useful guide to assist compound design in medicinal chemistry. It is well established that controlling size, lipophilicity, hydrogen bonding, flexibility and shape, guided by descriptors that approximate to these properties, can greatly increase the chances of successful drug discovery. Many therapeutic targets and new modalities are incompatible with the optimal ranges of these properties and thus there is much interest in approaches to find oral drug candidates outside of this space.
View Article and Find Full Text PDFQualitative research approaches were used to launch an international research collaboration between the U. S. and Cambodia.
View Article and Find Full Text PDFA major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding.
View Article and Find Full Text PDFHigh-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types.
View Article and Find Full Text PDFNF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome.
View Article and Find Full Text PDFHerein, we describe the development of a simple, high yielding and stereocontrolled strategy for the synthesis of a series of triazolopiperazines and other biologically relevant fused scaffolds from optically active amino acids. This route was applied to the synthesis of 22 scaffolds containing new, previously inaccessible vectors and used to access a novel analogue of ganaplacide.
View Article and Find Full Text PDFIn recent years the pharmaceutical industry has benefited from the advances made in fragment-based drug discovery (FBDD) with more than 30 fragment-derived drugs currently marketed or progressing through clinical trials. The success of fragment-based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries.
View Article and Find Full Text PDFWe describe semi-syntheses of the 11-hydroxyrotenoids sumatrol (1) and villosinol (2), starting from rotenone (5), using an oxime-directed C11-H functionalisation approach. Thus, rotenone (5) was converted into rotenone oxime (6), which gave dimeric palladacycle 7 following reaction with Na2PdCl4·3H2O. Controlled, divergent, oxidation of palladacycle 7 with either Pb(OAc)4 or K2Cr2O7 afforded the 11-acetoxylated intermediates 9 and 13, respectively, which were transformed into sumatrol (1) and villosinol (2).
View Article and Find Full Text PDFNeurobiological models of obesity postulate that obese individuals have difficulty regulating food intake partly because they attribute excessive salience to stimuli signaling food availability. Typically, human studies that investigate the relationship between brain responses to food-related stimuli and obesity present food cues without subsequent delivery of food. However, in order to identify the brain correlates of cue reactivity, we must record brain responses to food-related cues signaling food availability.
View Article and Find Full Text PDFAnimal-microbe co-evolution and symbiosis are broadly distributed across the animal kingdom. Insects form a myriad of associations with microbes ranging from vectoring of pathogens to intracellular, mutualistic relationships. Lower termites are key models for insect-microbe symbiosis because of the diversity, complexity and functionality of their unique tripartite symbiosis.
View Article and Find Full Text PDFThis work was motivated by subtidal observations of red urchins (Strongylocentrotus franciscanus) moving their spines into streamlined positions as water current increased in the field. Trials in a flume across flow speeds from 0 to 65 cm s(-1) enabled us to observe the change in overall shape of the urchins and quantify the decrease in spine angle that occurred as flow speeds increased. The effect of this behaviour on drag and lift was measured with physical models made from urchin tests with spines in the `up' position (typical in stagnant and slow velocities) and in the `down' position (typical of posture in high velocities).
View Article and Find Full Text PDFLike many reefs worldwide, reefs in French Polynesia are experiencing a shift from coral-dominated to algal-dominated systems. The macroalga Turbinaria ornata comprises the majority of the increasing algal biomass on the barrier reefs surrounding these islands, and its distribution is increasing throughout this region. Aspects of the ecomorphology of Turbinaria make it ideally suited to thrive under the physical conditions found across barrier reefs throughout French Polynesia.
View Article and Find Full Text PDFAn upright posture in the water column may expose benthic marine organisms to faster flow higher in the water column than near the substratum, potentially increasing rates of mass exchange while also exposing the organisms to higher hydrodynamic forces. Benthic organisms maintain upright postures in the water column by one of two mechanisms, stiffness or buoyancy. Turbinaria ornata is a tropical macroalga that uses either buoyancy or flexural stiffness (EI), depending on its flow habitat.
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