Biodiesel as a Sustainable Platform Chemical Enabled by Selective Partial Hydrogenation: Compounds Outplace Combustion?!

The hydrogenation of polyunsaturated fatty acids (PUFAs) in vegetable oils and their derivatives is essential for their use in many areas, such as biofuels and food chemistry. However, no attempts have been made to adapt this technology to the requirements of further chemical utilization of fatty acid methyl esters as molecular building blocks, especially for particularly promising double-bond reactions. In this work, we, therefore, use three homogeneous catalytic model reactions (hydroformylation, isomerizing methoxycarbonylation, and ethenolysis) to show, firstly, that it is already known from the literature that high PUFA contents have a negative impact on activity and selectivity. Subsequently, using the example of soybean and canola biodiesel, we demonstrate that these key figures can be drastically improved by a preceding selective partial hydrogenation. This makes it possible to first reduce the share of PUFAs to <1 w % without causing significant overhydrogenation and then to carry out hydroformylation, methoxycarbonylation, and ethenolysis with significantly increased activity (up to twentyfold) and selectivity (up to 80 % increase). With these findings, we hope to convince the scientific and industrial world of the potential of selective partial hydrogenation as a key technology for utilizing renewable raw materials and to encourage its effective use in future work.

Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.

Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial.

New DNA polymerase IIIC inhibitors: 3-subtituted anilinouracils with potent antibacterial activity in vitro and in vivo.

The development of resistance has rendered several antibiotics clinically ineffective, and there is an urgent medical need for potent and safe antibacterials with a novel and valid mode of action. To avoid cross-resistance, they should preferably inhibit targets that are not addressed by established antibiotics. In this respect, 6-anilinouracils represent a promising lead structure. They target the Gram-positive DNA polymerase IIIC, a target that is associated with a bactericidal mode of action. Moreover, they have no cross-resistance to marketed antibiotics. This paper describes the synthesis and biological characterization of structurally novel anilinouracils, some of which display potent in vivo efficacy in murine models of bacterial septicemia.

Improved synthesis of antibacterial 3-substituted 6-anilinouracils.

3-Substituted 6-anilinouracils, presently the most promising class of inhibitors of the bacterial DNA polymerase in Gram-positive bacteria, have been prepared by a general and straightforward three-step procedure starting from a readily available 1-benzyloxymethyl-protected derivative of 6-chlorouracil.

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment.

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.

Biological characterization of novel inhibitors of the gram-positive DNA polymerase IIIC enzyme.

Novel N-3-alkylated 6-anilinouracils have been identified as potent and selective inhibitors of bacterial DNA polymerase IIIC, the enzyme essential for the replication of chromosomal DNA in gram-positive bacteria. A nonradioactive assay measuring the enzymatic activity of the DNA polymerase IIIC in gram-positive bacteria has been assembled. The 6-anilinouracils described inhibited the polymerase IIIC enzyme at concentrations in the nanomolar range in this assay and displayed good in vitro activity (according to their MICs) against staphylococci, streptococci, and enterococci. The MICs of the most potent derivatives were about 4 microg/ml for this panel of bacteria. The 50% effective dose of the best compound (6-[(3-ethyl-4-methylphenyl)amino]-3-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}uracil) was 10 mg/kg of body weight after intravenous application in a staphylococcal sepsis model in mice, from which in vivo pharmacokinetic data were also acquired.

The nucleophilic addition of alpha-metallated 1,3-dioxanes to planar chiral cationic eta3-allylmolybdenum complexes. Synthesis of (2E,5S,6R,7E)-6-methyl-8-phenylocta-2,7-dienoic acid methyl ester, a key component of the Cryptophycins.

Two adjacent stereogenic centres and a pendant alkene were constructed via nucleophilic addition of a 1,3-dioxan-4-ylcopper(I) reagent to a cationic eta3-allylmolybdenum complex as part of a synthesis of (2E,5S,6R,7E)-6-methyl-8-phenylocta-2,7-dienoic acid, a key component of the Cryptophycins. Oxidative addition of Mo(CO)(4)(THF)(2) to allyl benzoates provides an efficient synthesis of eta3-allylmolybdenum(dicarbonyl) complexes.

The effect of midazolam on stress levels during simulated emergency medical service transport: a placebo-controlled, dose-response study.

UNLABELLED: Patients in the emergency medical service (EMS) may have increased endogenous catecholamines because of pain or fear and may benefit from sedation similar to premedication in the hospital. During a simulated EMS scene call, 72 healthy male volunteers were either transported by paramedics from a third-floor apartment through a staircase with subsequent EMS transport with sirens (three stress groups of n = 12; total, n = 36) or asked to sit on a chair for 5 min and lie down on a stretcher for 15 min (three control groups of n = 12; total, n = 36). Catecholamine plasma samples were measured in the respective stress and control groups at baseline and after placebo IV (n = 12) or 25 (n = 12) or 50 (n = 12) microg/kg of midazolam IV throughout the experiment, respectively. Statistical analysis was performed with analysis of variance; P < 0.05 was considered significant. The Placebo Stress versus Control group, but not the 50 microg/kg Stress Midazolam group, had both significantly increased epinephrine (73 +/- 5 pg/mL versus 45 +/- 5 pg/mL; P < 0.001) and norepinephrine (398 +/- 34 pg/mL versus 278 +/- 23 pg/mL; P < 0.01) plasma levels after staircase transport. After EMS transport, the Placebo Stress versus Control group had significantly increased epinephrine (51 +/- 4 pg/mL versus 37 +/- 4 pg/mL; P < 0.05) but not norepinephrine (216 +/- 24 pg/mL versus 237 +/- 18 pg/mL) plasma levels, whereas no significant differences in catecholamine plasma levels occurred between groups after either 25 or 50 microg/kg of midazolam. In conclusion, simulated EMS patients may be subject to more stress during staircase transport than during transport in an EMS vehicle. Titrating sedation with 25 microg/kg of midazolam significantly reduced endogenous catecholamines but not heart rate. IMPLICATIONS: Simulated emergency medical service patients were more likely to be stressed when being transported by paramedics through a staircase than in an ambulance. Accordingly, it may be beneficial to inject sedative drugs before initiating transport to ensure patient comfort and safety.