Stereospecific Palladium-Catalyzed C–H Arylation of Pyroglutamic Acid Derivatives at the C3 Position Enabled by 8‑Aminoquinoline as a Directing Group

An efficient and stereospecific Pd-catalyzed protocol for the C–H arylation of pyroglutamic acid derivatives that uses 8-aminoquinoline as a directing group is described. The reaction was shown to proceed efficiently with a variety of aryl and heteroaryl iodides bearing different functional groups, giving C3-arylated <i>cis</i> products in good to high yields. Removal of the 8-aminoquinoline unit from these C–H arylation products enables access to synthetically useful <i>cis</i> and <i>trans</i> pyroglutamic acid-based building blocks

Stereospecific Palladium-Catalyzed C–H Arylation of Pyroglutamic Acid Derivatives at the C3 Position Enabled by 8‑Aminoquinoline as a Directing Group

An efficient and stereospecific Pd-catalyzed protocol for the C–H arylation of pyroglutamic acid derivatives that uses 8-aminoquinoline as a directing group is described. The reaction was shown to proceed efficiently with a variety of aryl and heteroaryl iodides bearing different functional groups, giving C3-arylated <i>cis</i> products in good to high yields. Removal of the 8-aminoquinoline unit from these C–H arylation products enables access to synthetically useful <i>cis</i> and <i>trans</i> pyroglutamic acid-based building blocks

Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit P. falciparum Dihydroorotate Dehydrogenase

Dihydroorotate dehydrogenase (DHODH) is an enzyme necessary for pyrimidine biosynthesis in protozoan parasites of the genus Plasmodium, the causative agents of malaria. We recently reported the identification of novel compounds derived from diversity-oriented synthesis with activity in multiple stages of the malaria parasite life cycle. Here, we report the optimization of a potent series of antimalarial inhibitors consisting of azetidine-2-carbonitriles, which we had previously shown to target P. falciparum DHODH in a biochemical assay. Optimized compound BRD9185 (27) has in vitro activity against multidrug-resistant blood-stage parasites (EC50 = 0.016 μM) and is curative after just three doses in a P. berghei mouse model. BRD9185 has a long half-life (15 h) and low clearance in mice and represents a new structural class of DHODH inhibitors with potential as antimalarial drugs

Distortion Metrics for Robotic Sensor Networks

Abstract — We examine the problem of planning the trajectory of a robotic vehicle to gather data from a deployment of stationary sensors. The robotic vehicle and the sensors are equipped with wireless modems (e.g., radio in terrestrial environments or acoustic in underwater environments), which provide noisy communication across limited distances. In such scenarios, the robotic vehicle can improve its efficiency by planning an informed data gathering trajectory. Prior work has proposed information theoretic performance metrics for these problems based on mutual information, but such metrics do not properly account for stochastic variations in the quantity being measured. We propose a novel performance metric for data gathering in robotic sensor networks based on the concept of squared error distortion. This metric provides a principled approach for modeling source variations and communication limitations during data collection. We analyze the formal properties of the distortion function, and we propose a sampling-based motion planning algorithm for optimizing data gathering tours for minimal distortion. We compare the proposed algorithms in simulation, and we show that distortion metrics provide significant improvements in data gathering efficiency. I

Discovery of Antimalarial Azetidine-2-carbonitriles That Inhibit <i>P. falciparum</i> Dihydroorotate Dehydrogenase

Dihydroorotate dehydrogenase (DHODH) is an enzyme necessary for pyrimidine biosynthesis in protozoan parasites of the genus <i>Plasmodium</i>, the causative agents of malaria. We recently reported the identification of novel compounds derived from diversity-oriented synthesis with activity in multiple stages of the malaria parasite life cycle. Here, we report the optimization of a potent series of antimalarial inhibitors consisting of azetidine-2-carbonitriles, which we had previously shown to target <i>P. falciparum</i> DHODH in a biochemical assay. Optimized compound BRD9185 (<b>27</b>) has <i>in vitro</i> activity against multidrug-resistant blood-stage parasites (EC₅₀ = 0.016 μM) and is curative after just three doses in a <i>P. berghei</i> mouse model. BRD9185 has a long half-life (15 h) and low clearance in mice and represents a new structural class of DHODH inhibitors with potential as antimalarial drugs

High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria

In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. Achieving this throughput necessitates the development of efficient ultra-high-throughput screening methods. Here, we report the development and evaluation of a luciferase-based phenotypic screen of malaria exoerythrocytic-stage parasites optimized for a 1536-well format. This assay uses the exoerythrocytic stage of the rodent malaria parasite, Plasmodium berghei, and a human hepatoma cell line. We use this assay to evaluate several biased and unbiased compound libraries, including two small sets of molecules (400 and 89 compounds, respectively) with known activity against malaria erythrocytic-stage parasites and a set of 9886 diversity-oriented synthesis (DOS)-derived compounds. Of the compounds screened, we obtain hit rates of 12–13 and 0.6% in preselected and naïve libraries, respectively, and identify 52 compounds with exoerythrocytic-stage activity less than 1 μM and having minimal host cell toxicity. Our data demonstrate the ability of this method to identify compounds known to have causal prophylactic activity in both human and animal models of malaria, as well as novel compounds, including some exclusively active against parasite exoerythrocytic stages

High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria

In order to identify the most attractive starting points for drugs that can be used to prevent malaria, a diverse chemical space comprising tens of thousands to millions of small molecules may need to be examined. Achieving this throughput necessitates the development of efficient ultra-high-throughput screening methods. Here, we report the development and evaluation of a luciferase-based phenotypic screen of malaria exoerythrocytic-stage parasites optimized for a 1536-well format. This assay uses the exoerythrocytic stage of the rodent malaria parasite, Plasmodium berghei, and a human hepatoma cell line. We use this assay to evaluate several biased and unbiased compound libraries, including two small sets of molecules (400 and 89 compounds, respectively) with known activity against malaria erythrocytic-stage parasites and a set of 9886 diversity-oriented synthesis (DOS)-derived compounds. Of the compounds screened, we obtain hit rates of 12–13 and 0.6% in preselected and naïve libraries, respectively, and identify 52 compounds with exoerythrocytic-stage activity less than 1 μM and having minimal host cell toxicity. Our data demonstrate the ability of this method to identify compounds known to have causal prophylactic activity in both human and animal models of malaria, as well as novel compounds, including some exclusively active against parasite exoerythrocytic stages

Association of leptin, 25-hydroxyvitamin D, and parathyroid hormone in women.

Vitamin D deficiency and adipocytokines have been implicated in the etiology of aging-related diseases such as cancer, osteoporosis, and diseases of the cardiovascular system. The association between elevated parathyroid hormone (PTH) and low 25-hydroxyvitamin D (25-OH-VitD) in plasma is used to define vitamin D deficiency, yet their associated mechanistic pathways are unclear. Utilizing plasma samples from women in a previous intervention study, we measured plasma 25-OH-VitD, leptin, adiponectin, PTH, and lipid levels. We observed strong positive associations for leptin with PTH, gamma -tocopherol, and body mass index (BMI) and inverse associations with 25-OH-VitD and adiponectin. Although commonly accepted that vitamin D deficiency causes hyperparathyroidism, we observed this association primarily in individuals with elevated leptin levels, suggesting that leptin may be an important modifier of this effect consistent with 25-OH-VitD-mediated inhibition of leptin. Leptin was highly correlated with the BMI/25-OH-VitD ratio (r = 0.80; P < 0.0001), consistent with a model in which BMI (adiposity) and 25-OH-VitD are the primary determinants of circulating leptin and PTH levels. This model may explain the failure of some studies to observe elevated PTH in vitamin D deficient adolescents and provides important insight into epidemiological studies exploring the associations of these individual biomarkers with chronic disease risk and mortality

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors

Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets