ABSTRACT
The heterodifunctionalization of alkenes is an efficient method for synthesizing highly functionalized organic molecules. In this report, we describe the use of anodically coupled electrolysis for the catalytic chloroalkylation of alkenes-a reaction that constructs vicinal C-C and C-Cl bonds in a single synthetic operation-from malononitriles or cyanoacetates and NaCl. Knowledge of the persistent radical effect guided the reaction design and development. A series of controlled experiments, including divided-cell electrolysis that compartmentalized the anodic and cathodic events, allowed us to identify the key radical intermediates and the pathway to their electrocatalytic formation. Cyclic voltammetry data further support the proposed mechanism entailing the parallel, Mn-mediated generation of two radical intermediates in an anodically coupled electrolysis followed by their selective addition to the alkene.
ABSTRACT
Electrocatalysis was employed to promote Diels-Alder reactions between electronically mismatched substrates. A catalytic amount of electricity was enough to complete the overall reactions and GC-MS monitoring and CV measurements clearly illustrated the electrocatalytic nature of the reactions, which involve an EC-backward-E mechanism. The electrocatalytic Diels-Alder reactions were rationally designed based on the concept of redox tags. The results were supported by DFT calculations.
ABSTRACT
PURPOSE: In the present study, the nonclinical safety profile of tolvaptan was evaluated. METHODS: A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs. RESULTS: In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems. In general toxicity studies, a single dose of tolvaptan up to 2,000 mg/kg was not lethal in rats and dogs. Tolvaptan did not cause any target organ toxicity in rats after treatment for 26 weeks or in dogs after treatment for 52 weeks at oral doses of up to 1,000 mg/kg/day. The toxicities observed in the present studies were generally attributable to the exaggerated pharmacological action of tolvaptan. In reproductive and developmental toxicity studies in rats, fertility was not affected. Suppressed viability or growth observed in the prenatal and postnatal progeny occurred at the maternally toxic dose of 1,000 mg/kg/day. In rabbits, tolvaptan showed teratogenicity at 1,000 mg/kg/day, a dose that was maternally toxic causing abortion. Tolvaptan was not genotoxic or carcinogenic, and did not induce phototoxicity, antigenicity or immunotoxicity. CONCLUSION: Nonclinical toxicity that precludes the safe administration of tolvaptan to humans was not observed. However, appropriate cautions should be taken in women of childbearing potential.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/pharmacology , Benzazepines/toxicity , Diuretics/pharmacology , Diuretics/toxicity , Animals , Blood Pressure/drug effects , CHO Cells , Central Nervous System/drug effects , Cricetinae , Cricetulus , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/physiology , Female , Femoral Artery/drug effects , Femoral Artery/physiology , Guinea Pigs , Heart Rate/drug effects , Ileum/drug effects , Ileum/physiology , In Vitro Techniques , Male , Mice , Mice, Inbred ICR , Muscle Contraction/drug effects , Peripheral Nervous System/drug effects , Pregnancy , Rabbits , Rats , Rats, Sprague-Dawley , Regional Blood Flow/drug effects , Respiration/drug effects , Stomach/drug effects , Stomach/physiology , TolvaptanABSTRACT
We have developed a method for measuring the temperature of micro-regions in aqueous solutions using near-infrared spectroscopy that enables us to measure the temperature of biological cells, tissues, and biochemical solutions in vitro. The measurement principle is based on the fact that the peak wavelength of the water absorption band with its center near 1450 nm shifts with changes in temperature. The measurement system, which consists of a biological microscope and two spectrophotometers, can measure respective absorbance spectra for two areas that are each 80 microm in diameter. We formed the temperature distribution in a 500-microm thick water film by heating an immersed Nichrome wire and measured the temperature difference between the two areas. The results of the measurement were compared to a calculated temperature distribution.
Subject(s)
Hot Temperature , Spectrophotometry, Infrared/methods , WaterABSTRACT
A carboxyethylester-polyrotaxane was synthesized as a novel calcium chelating polymer in the field of oral drug delivery and characterized in terms of mechanism of trypsin inhibition. Here, carboxyethylester (CEE) groups are introduced to all the primary hydroxyl groups in alpha-cyclodextrins (alpha-CDs), which are threaded onto a poly(ethylene glycol) chain capped with bulky end-groups (polyrotaxane). The solubility of the CEE-polyrotaxane in physiological conditions increased with pH, indicating ionization-related solubility similar to conventional polyacrylates. The ability of calcium (Ca2+) chelation was found to increase in the order of poly(acrylic acid) (PAA)>CEE-polyrotaxanez.Gt;CEE-alpha-CD, suggesting that the increased density of carboxyl groups enhances the Ca2+ chelating ability. The activity of trypsin was inhibited by these compounds in the same order of the calcium chelation. However, the inhibitory effect of CEE-polyrotaxane was reduced by adding excess Ca2+ without precipitation that was observed in the presence of PAA. Such the reduced inhibition and precipitation by CEE-alpha-CD was not observed. Therefore, the inhibitory effect of CEE-polyrotaxane is due to Ca2+ chelation from trypsin without non-specific interaction.