Litium 1,3-ditiaanien ja ditioasetaalien aerobinen hapetus

Lithiated compounds are well known to be reactive towards oxygen. The initial studies conducted at Tampere University of Technology had shown that upon exposure of 2-aryl-2-lithio-1,3-dithianes to air, three equivalents of 1,3-dithianes undergo an autooxidative condensation forming previously unreported products in good yields. Since only cyclic 2-aryl-1,3-dithianes were previously studied, the objective of this thesis was to study whether the scope of the oxidation reaction could be extended to acyclic lithiated benzaldehyde dithioacetals and 2-alkyl-1,3-dithianes. The study was performed by preparing the dithioacetals and 1,3-dithianes and then oxidizing the lithiated substrates. The results of the oxidation reactions were evaluated by determining the structures of isolated products by using NMR and mass spectrometry and then comparing the relative yields of the products. The aerobic oxidations of lithiated benzaldehyde dithioacetals derived from primary, secondary and benzene thiols yielded alpha-sulfide ketones and orthothioesters. The observed products were analogous to the products obtained from the oxidations of 2-aryl-2-lithio-1,3-dithianes, which indicated that the same autooxidative condensation mechanism operated. When lithiated n-butylthiol dithioacetal was oxidized, an excellent 97% yield of alpha-sulfide ketone and 72% yield of orthothioester was obtained. When dithioacetals derived from secondary or benzene thiols were used, the observed yields decreased significantly, which was likely due to increased steric hindrance. The oxidation of tert-butylthiol dithioacetal afforded a thioester in 62% yield, which suggested that the oxidation mechanism proceeds by forming an initial thioester intermediate. Bulky tert-butyl probably prevented further condensations from occurring. Dithioacetal derived from benzylic thiol was observed to form an unexpected product upon treatment with n-butyllithium. This could be a result of an anionic rearrangement, however, further studies are required to confirm the observation. Oxidations of 2-alkyl-2-lithio-1,3-dithianes afforded 1,2-diketone derivatives where the other carbonyl was still protected as a 1,3-dithiane. While the yields of the derivatives were poor, the observed structures provided more information about the mechanism of the oxidation. It is likely that the obtained products resulted from an attack of excess lithiated 1,3-dithiane to the thioester intermediate. In contrast to 2-aryl-1,3-dithiane, the reaction halted after after the first condensation because the formation of a lithium enolate likely competed with the second condensation. As with tert-butylthiol dithioacetal, the oxidation of lithiated 2-tert-butyl-1,3-dithiane was observed to halt at the thioester intermediate, which was likely due to similar steric reasons. Despite the high value of 1,3-dithianes in synthetic chemistry, the work described herein presents an insight into one of the main limitations in using of 2-lithio-1,3-dithianes, namely previously reported inconsistent yields and formation of byproducts

The N-methyl-D -aspartate antagonist memantine has no neuroprotective effect during hypothermic circulatory arrest: A study in the chronic porcine model

AbstractBackground: Glutamate excitotoxicity has an important role in the development of brain injury after prolonged hypothermic circulatory arrest. The goal of the present study was to determine the potential efficacy of memantine, an N -methyl-D -aspartate receptor antagonist, to mitigate cerebral injury after hypothermic circulatory arrest. Methods: Twenty pigs (23-33 kg) were randomly assigned to receive memantine (5 mg/kg) or placebo in a blinded fashion before a 75-minute period of hypothermic circulatory arrest at 20°C. Hemodynamic, electroencephalographic, and metabolic monitoring were carried out. The intracerebral concentrations of glucose, lactate, glutamate, and glycerol were measured by means of enzymatic methods on a microdialysis analyzer. Daily behavioral assessment was performed until the animals died or were put to death on day 7. Histologic analysis of the brain was carried out in all animals. Results: In the memantine group, 5 of 10 animals survived 7 days compared with 9 of 10 in the placebo group. The median behavioral score at day 7 was 3.5 in the memantine group and 7.5 in the placebo group (P >.2). Among the surviving animals, medians were 9.0 and 8.0 on day 7 (P >.2), respectively. The medians of recovered electroencephalographic bursts were equal in both groups. The median of total histopathologic score was 16 in the memantine group and 14 in the placebo group (P >.2). There was a negative correlation between glutamate levels and electroencephalographic burst recovery (τ = –0.377, P =.043). A positive correlation was found between the highest individual glutamate value and histopathologic score (τ = 0.336, P =.045). Conclusions: The present study demonstrates that memantine has no neuroprotective effect after hypothermic circulatory arrest in the pig. In addition, we have shown the accuracy of cerebral glutamate measurements to predict histopathologic injury after hypothermic ischemia. (J Thorac Cardiovasc Surg 2001;121:957-70

Prolonged mild hypothermia after experimental hypothermic circulatory arrest in a chronic porcine model

AbstractObjectives: We sought to evaluate the potential efficacy of prolonged mild hypothermia after hypothermic circulatory arrest. Methods: Twenty pigs, after a 75-minute period of hypothermic circulatory arrest, were randomly assigned to be rewarmed to 37°C (normothermia group) or to 32°C and kept at that temperature for 14 hours from the start of rewarming (hypothermia group). Results: The 7-day survival was 30% in the hypothermia group and 70% in the normothermia group (P =.08). The hypothermia group had poorer postoperative behavioral scores than the normothermia group. Prolonged hypothermia was associated with lower oxygen extraction and consumption rates and higher mixed venous oxygen saturation levels during the first hours after hypothermic circulatory arrest. Decreased cardiac index, lower pH, and higher partial pressure of carbon dioxide were observed in the hypothermia group. There was a trend for beneficial effect of prolonged hypothermia in terms of lower brain lactate levels until the 4-hour interval and of intracranial pressure until the 10-hour interval. Postoperatively, total leukocyte and neutrophil counts were lower, and creatine kinase BB was significantly increased in the hypothermia group. At extubation, the hypothermia group had higher oxygen extraction rates and lower brain tissue oxygen tension. Conclusions: A 14-hour period of mild hypothermia after 75-minute hypothermic circulatory arrest seems to be associated with poor outcome. However, the results of this study suggest that mild hypothermia may preserve its efficacy when it is used for no longer than 4 hours, but the potentials of a shorter period of postoperative mild hypothermia still require further investigation.J Thorac Cardiovasc Surg 2002;123:724-3

Increased antibacterial properties of indoline-derived phenolic Mannich bases

The search for antibacterial agents for the combat of nosocomial infections is a timely problem, as antibiotic-resistant bacteria continue to thrive. The effect of indoline substituents on the antibacterial properties of aminoalkylphenols was studied, leading to the development of a library of compounds with minimum inhibitory concentrations (MICs) as low as 1.18 μM. Two novel aminoalkylphenols were identified as particularly promising, after MIC and minimum bactericidal concentrations (MBC) determination against a panel of reference strain Gram-positive bacteria, and further confirmed against 40 clinical isolates (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes). The same two aminoalkylphenols displayed low toxicity against two in vivo models (Artemia salina brine shrimp and Saccharomyces cerevisiae). The in vitro cytotoxicity evaluation (on human keratinocytes and human embryonic lung fibroblast cell lines) of the same compounds was also carried out. They demonstrated a particularly toxic effect on the fibroblast cell lines, with IC50 in the 1.7-5.1 μM range, thus narrowing their clinical use. The desired increase in the antibacterial properties of the aminoalkylphenols, particularly indoline-derived phenolic Mannich bases, was reached by introducing an additional nitro group in the indolinyl substituent or by the replacement of a methyl by a bioisosteric trifluoromethyl substituent in the benzyl group introduced through use of boronic acids in the Petasis borono-Mannich reaction. Notably, the introduction of an additional nitro moiety did not confer added toxicity to the aminoalkylphenols.acceptedVersionPeer reviewe

Litium 1,3-ditiaanien ja ditioasetaalien aerobinen hapetus

Lithiated compounds are well known to be reactive towards oxygen. The initial studies conducted at Tampere University of Technology had shown that upon exposure of 2-aryl-2-lithio-1,3-dithianes to air, three equivalents of 1,3-dithianes undergo an autooxidative condensation forming previously unreported products in good yields. Since only cyclic 2-aryl-1,3-dithianes were previously studied, the objective of this thesis was to study whether the scope of the oxidation reaction could be extended to acyclic lithiated benzaldehyde dithioacetals and 2-alkyl-1,3-dithianes. The study was performed by preparing the dithioacetals and 1,3-dithianes and then oxidizing the lithiated substrates. The results of the oxidation reactions were evaluated by determining the structures of isolated products by using NMR and mass spectrometry and then comparing the relative yields of the products. The aerobic oxidations of lithiated benzaldehyde dithioacetals derived from primary, secondary and benzene thiols yielded alpha-sulfide ketones and orthothioesters. The observed products were analogous to the products obtained from the oxidations of 2-aryl-2-lithio-1,3-dithianes, which indicated that the same autooxidative condensation mechanism operated. When lithiated n-butylthiol dithioacetal was oxidized, an excellent 97% yield of alpha-sulfide ketone and 72% yield of orthothioester was obtained. When dithioacetals derived from secondary or benzene thiols were used, the observed yields decreased significantly, which was likely due to increased steric hindrance. The oxidation of tert-butylthiol dithioacetal afforded a thioester in 62% yield, which suggested that the oxidation mechanism proceeds by forming an initial thioester intermediate. Bulky tert-butyl probably prevented further condensations from occurring. Dithioacetal derived from benzylic thiol was observed to form an unexpected product upon treatment with n-butyllithium. This could be a result of an anionic rearrangement, however, further studies are required to confirm the observation. Oxidations of 2-alkyl-2-lithio-1,3-dithianes afforded 1,2-diketone derivatives where the other carbonyl was still protected as a 1,3-dithiane. While the yields of the derivatives were poor, the observed structures provided more information about the mechanism of the oxidation. It is likely that the obtained products resulted from an attack of excess lithiated 1,3-dithiane to the thioester intermediate. In contrast to 2-aryl-1,3-dithiane, the reaction halted after after the first condensation because the formation of a lithium enolate likely competed with the second condensation. As with tert-butylthiol dithioacetal, the oxidation of lithiated 2-tert-butyl-1,3-dithiane was observed to halt at the thioester intermediate, which was likely due to similar steric reasons. Despite the high value of 1,3-dithianes in synthetic chemistry, the work described herein presents an insight into one of the main limitations in using of 2-lithio-1,3-dithianes, namely previously reported inconsistent yields and formation of byproducts

Pot-Economy Autooxidative Condensation of 2-Aryl-2-lithio-1,3-dithianes

The autoxidative condensation of 2-aryl-2-lithio-1,3-dithianes is here reported. Treatment of 2-aryl-1,3-dithianes with n-BuLi in the absence of any electrophile leads to condensation of three molecules of 1,3-dithianes and formation of highly functionalized α-thioether ketones orthothioesters in 51–89% yields upon air exposure. The method was further expanded to benzaldehyde dithioacetals, affording corresponding orthothioesters and α-thioether ketones in 48–97% yields. The experimental results combined with density functional theory studies support a mechanism triggered by the autoxidation of 2-aryl-2-lithio-1,3-dithianes to yield a highly reactive thioester that undergoes condensation with two other molecules of 2-aryl-2-lithio-1,3-dithiane.peerReviewe

Aminobenzylated 4-Nitrophenols as Antibacterial Agents Obtained from 5-Nitrosalicylaldehyde through a Petasis Borono-Mannich Reaction

Multidrug-resistant bacteria are one of the current biggest threats to public health and are responsible for most nosocomial infections. Herein, we report the efficient and facile synthesis of antibacterial agents aminoalkylphenols, derived from 5-nitrosalicyladehyde and prepared through a Petasis borono-Mannich multicomponent reaction. Minimum inhibitory concentrations (MICs) as low as 1.23 μM for a chlorine derivative were determined for multidrug-resistant Gram-positive bacteria, namely, Staphylococcus aureus and Enterococcus faecalis, two of the main pathogens responsible for infections in a hospital environment. The most promising antibacterial agents were further tested against eight strains of four Gram-positive species in order to elucidate their antibacterial broadness. In vitro cytotoxicity assays of the most active aminoalkylphenol revealed considerably lower toxicity against mammalian cells, as concentrations one order of magnitude higher than the determined MICs were required to induce human keratinocyte cell death. The phenol moiety was verified to be important in deeming the antibacterial properties of the analyzed compounds, although no correlation between such properties and their antioxidant activity was observed. A density functional theory computational study substantiated the ability of aminoalkylphenols to serve as precursors of ortho-quinone methides.publishedVersionPeer reviewe