ABSTRACT
An unprecedented visible light-assisted and zinc triflate-catalyzed construction of a diaryl-substituted quaternary stereocenter is reported. 2-(4-Hydroxyphenyl)-substituted aldehydes and ketones have been prepared in moderate to high yields via multicomponent reaction of acetylene, benzoquinone (BQ), and indole/aniline/thiol. The reaction is believed to proceed via in situ generation of p-quinone methide through a [2+2] cycloaddition-retroelectrocyclization of BQ and acetylene in blue light followed by a zinc triflate-catalyzed vinylogous Michael addition reaction with nucleophiles.
ABSTRACT
Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Brain/metabolism , Dacarbazine/analogs & derivatives , Animals , Antineoplastic Agents, Alkylating/blood , Antineoplastic Agents, Alkylating/pharmacokinetics , Area Under Curve , Cell Line, Tumor , Chromatography, Liquid , Dacarbazine/blood , Dacarbazine/pharmacokinetics , Dacarbazine/pharmacology , Humans , Rats , Tandem Mass Spectrometry , TemozolomideABSTRACT
AIM: Neurocognitive dysfunction continues to be the bane of open heart surgery despite vast improvements in surgical, anesthetic, and postoperative management. This observational cohort study was carried out to evaluate the efficacy of intraoperative CO2 insufflation by the field flooding technique in reducing postoperative neurocognitive dysfunction. METHODS: Three hundred randomly selected patients undergoing open heart surgery were observed: 150 (group A) were exposed to CO2 insufflation, and the other 150 (group B) were not exposed to CO2. Anesthetic, cardiopulmonary bypass, and myocardial protection techniques were standardized and similar in both groups. Neurocognitive function tests were performed preoperatively, 1 week postoperatively, and after 1 month. RESULTS: The analysis revealed that neurocognitive dysfunction occurred in 8 of 150 patients in group A (incidence p1 = 0.053) and 27 of 150 in group B (incidence p2 = 0.18). The relative risk of neurocognitive dysfunction was 0.30 (p = 0.001, 95% confidence interval 0.14-0.63), implying that CO2 insufflation is protective against neurocognitive dysfunction. The risk difference was 0.13 (p2-p1); this implies that 13% of patients can be prevented from developing neurocognitive dysfunction if exposed to CO2. CONCLUSION: This study confirms the known advantage of the relatively underutilized practice of CO2 insufflation. We recommend that CO2 insufflation be performed in all open heart surgery cases to bring down the incidence of neurocognitive dysfunction. This technique is simple to use without any major paraphernalia or additional cost.
Subject(s)
Carbon Dioxide/administration & dosage , Cardiac Surgical Procedures , Insufflation/methods , Neurocognitive Disorders , Postoperative Complications , Adult , Cardiac Surgical Procedures/adverse effects , Cardiac Surgical Procedures/methods , Cardiopulmonary Bypass/methods , Female , Humans , Intelligence Tests , Intraoperative Care/methods , Male , Middle Aged , Neurocognitive Disorders/diagnosis , Neurocognitive Disorders/etiology , Neurocognitive Disorders/prevention & control , Neuropsychological Tests , Postoperative Complications/diagnosis , Postoperative Complications/prevention & control , Treatment OutcomeABSTRACT
We experimentally investigate the mechanism of formation of self-assembled arrays of nanoislands surrounding dopant sources on the (001) surface of yttria-stabilized zirconia. Initially, we used lithographically defined thin-film patches of gadolinia-doped ceria (GDC) as dopant sources. During annealing at approximately one-half the melting temperature of zirconia, surface diffusion of dopants leads to the breakup of the surface around the source, creating arrays of epitaxial nanoislands with a characteristic size (~100 nm) and alignment along elastically compliant directions, <110>. The breakup relieves elastic strain energy at the expense of increasing surface energy. On the basis of understanding the mechanism of island formation, we introduce a simple and versatile powder-based doping process for spontaneous surface patterning. The new process bypasses lithography and conventional vapor-source doping, opening the door to spontaneous surface patterning of functional ceramics and other refractory materials. In addition to using GDC solid-solution powders, we demonstrate the effectiveness of the process in another system based on Eu2O3.
