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Peter J. Roth - One of the best experts on this subject based on the ideXlab platform.
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Azide–para-Fluoro Substitution on Polymers: Multipurpose Precursors for Efficient Sequential Postpolymerization Modification
Macromolecules, 2019Co-Authors: Janina-miriam Noy, Willi Smolan, Peter J. RothAbstract:The 2,3,4,5,6-pentafluorobenzyl group has become a popular reactive functionality in polymer chemistry because of its high susceptibility to para-fluoro substitution with thiols. Herein, it is demonstrated postpolymerization that the para-fluoride can be substituted using sodium azide and that the resulting 4-azido-2,3,5,6-tetrafluorobenzyl-functional polymers are versatile precursors for a multitude of onward modifications with click-like efficiencies. Quantitative azide–para-fluoro substitution was found for poly(2,3,4,5,6-pentafluorobenzyl methacrylate) and the related Passerini ester–amide (meth)acrylic (co)polymers when heated in DMF with sodium azide to 80 °C for 60–90 min. Conversely, the azidation of poly(2,3,4,5,6-pentafluorostyrene) under similar conditions resulted in ~90% substitution efficiency. Azide-functional (co-)polymers were thermally stable below 100 °C and were subsequently modified with (i) four different alkynes (CuBr, triethylamine, DMF, 55 °C, overnight) to give 1,4-substituted 1,2,3-triazoles in >95% conversions; (ii) potassium thioacetate (DMF, RT, 15 min) with quantitative amidation to the Acetanilide Derivative; and (iii) DL-dithiothreitol (methanol/DMF, RT, 90 min) resulting in complete reduction of the azides to primary amines, which were subsequently acylated with two different acyl chlorides. Products were characterized by 1H NMR, 19F NMR, and FT-IR spectroscopies, and size exclusion chromatography. Given their adaptability, perfluorophenylazides have large potential as multi-purpose intermediates in polymer and materials chemistry.
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Azide–para-Fluoro Substitution on Polymers: Multipurpose Precursors for Efficient Sequential Postpolymerization Modification
2019Co-Authors: Janina-miriam Noy, Willi Smolan, Peter J. RothAbstract:The 2,3,4,5,6-pentafluorobenzyl group has become a popular reactive functionality in polymer chemistry because of its high susceptibility to para-fluoro substitution with thiols. Herein, it is demonstrated postpolymerization that the para-fluoride can be substituted using sodium azide and that the resulting 4-azido-2,3,5,6-tetrafluorobenzyl-functional polymers are versatile precursors for a multitude of onward modifications with click-like efficiencies. Quantitative azide–para-fluoro substitution was found for poly(2,3,4,5,6-pentafluorobenzyl methacrylate) and the related Passerini ester–amide (meth)acrylic (co)polymers when heated in DMF with sodium azide to 80 °C for 60–90 min. Conversely, the azidation of poly(2,3,4,5,6-pentafluorostyrene) under similar conditions resulted in ∼90% substitution efficiency. Azide-functional (co-)polymers were thermally stable below 100 °C and were subsequently modified with (i) four different alkynes (CuBr, triethylamine, DMF, 55 °C, overnight) to give 1,4-substituted 1,2,3-triazoles in >95% conversions; (ii) potassium thioacetate (DMF, RT, 15 min) with quantitative amidation to the Acetanilide Derivative; and (iii) dl-dithiothreitol (methanol/DMF, RT, 90 min), resulting in complete reduction of the azides to primary amines, which were subsequently acylated with two different acyl chlorides. Products were characterized by 1H NMR, 19F NMR, Fourier transform infrared spectroscopies, and size exclusion chromatography. Given their adaptability, perfluorophenylazides have huge potential as multipurpose intermediates in polymer and materials chemistry
Janina-miriam Noy - One of the best experts on this subject based on the ideXlab platform.
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Azide–para-Fluoro Substitution on Polymers: Multipurpose Precursors for Efficient Sequential Postpolymerization Modification
Macromolecules, 2019Co-Authors: Janina-miriam Noy, Willi Smolan, Peter J. RothAbstract:The 2,3,4,5,6-pentafluorobenzyl group has become a popular reactive functionality in polymer chemistry because of its high susceptibility to para-fluoro substitution with thiols. Herein, it is demonstrated postpolymerization that the para-fluoride can be substituted using sodium azide and that the resulting 4-azido-2,3,5,6-tetrafluorobenzyl-functional polymers are versatile precursors for a multitude of onward modifications with click-like efficiencies. Quantitative azide–para-fluoro substitution was found for poly(2,3,4,5,6-pentafluorobenzyl methacrylate) and the related Passerini ester–amide (meth)acrylic (co)polymers when heated in DMF with sodium azide to 80 °C for 60–90 min. Conversely, the azidation of poly(2,3,4,5,6-pentafluorostyrene) under similar conditions resulted in ~90% substitution efficiency. Azide-functional (co-)polymers were thermally stable below 100 °C and were subsequently modified with (i) four different alkynes (CuBr, triethylamine, DMF, 55 °C, overnight) to give 1,4-substituted 1,2,3-triazoles in >95% conversions; (ii) potassium thioacetate (DMF, RT, 15 min) with quantitative amidation to the Acetanilide Derivative; and (iii) DL-dithiothreitol (methanol/DMF, RT, 90 min) resulting in complete reduction of the azides to primary amines, which were subsequently acylated with two different acyl chlorides. Products were characterized by 1H NMR, 19F NMR, and FT-IR spectroscopies, and size exclusion chromatography. Given their adaptability, perfluorophenylazides have large potential as multi-purpose intermediates in polymer and materials chemistry.
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Azide–para-Fluoro Substitution on Polymers: Multipurpose Precursors for Efficient Sequential Postpolymerization Modification
2019Co-Authors: Janina-miriam Noy, Willi Smolan, Peter J. RothAbstract:The 2,3,4,5,6-pentafluorobenzyl group has become a popular reactive functionality in polymer chemistry because of its high susceptibility to para-fluoro substitution with thiols. Herein, it is demonstrated postpolymerization that the para-fluoride can be substituted using sodium azide and that the resulting 4-azido-2,3,5,6-tetrafluorobenzyl-functional polymers are versatile precursors for a multitude of onward modifications with click-like efficiencies. Quantitative azide–para-fluoro substitution was found for poly(2,3,4,5,6-pentafluorobenzyl methacrylate) and the related Passerini ester–amide (meth)acrylic (co)polymers when heated in DMF with sodium azide to 80 °C for 60–90 min. Conversely, the azidation of poly(2,3,4,5,6-pentafluorostyrene) under similar conditions resulted in ∼90% substitution efficiency. Azide-functional (co-)polymers were thermally stable below 100 °C and were subsequently modified with (i) four different alkynes (CuBr, triethylamine, DMF, 55 °C, overnight) to give 1,4-substituted 1,2,3-triazoles in >95% conversions; (ii) potassium thioacetate (DMF, RT, 15 min) with quantitative amidation to the Acetanilide Derivative; and (iii) dl-dithiothreitol (methanol/DMF, RT, 90 min), resulting in complete reduction of the azides to primary amines, which were subsequently acylated with two different acyl chlorides. Products were characterized by 1H NMR, 19F NMR, Fourier transform infrared spectroscopies, and size exclusion chromatography. Given their adaptability, perfluorophenylazides have huge potential as multipurpose intermediates in polymer and materials chemistry
Willi Smolan - One of the best experts on this subject based on the ideXlab platform.
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Azide–para-Fluoro Substitution on Polymers: Multipurpose Precursors for Efficient Sequential Postpolymerization Modification
Macromolecules, 2019Co-Authors: Janina-miriam Noy, Willi Smolan, Peter J. RothAbstract:The 2,3,4,5,6-pentafluorobenzyl group has become a popular reactive functionality in polymer chemistry because of its high susceptibility to para-fluoro substitution with thiols. Herein, it is demonstrated postpolymerization that the para-fluoride can be substituted using sodium azide and that the resulting 4-azido-2,3,5,6-tetrafluorobenzyl-functional polymers are versatile precursors for a multitude of onward modifications with click-like efficiencies. Quantitative azide–para-fluoro substitution was found for poly(2,3,4,5,6-pentafluorobenzyl methacrylate) and the related Passerini ester–amide (meth)acrylic (co)polymers when heated in DMF with sodium azide to 80 °C for 60–90 min. Conversely, the azidation of poly(2,3,4,5,6-pentafluorostyrene) under similar conditions resulted in ~90% substitution efficiency. Azide-functional (co-)polymers were thermally stable below 100 °C and were subsequently modified with (i) four different alkynes (CuBr, triethylamine, DMF, 55 °C, overnight) to give 1,4-substituted 1,2,3-triazoles in >95% conversions; (ii) potassium thioacetate (DMF, RT, 15 min) with quantitative amidation to the Acetanilide Derivative; and (iii) DL-dithiothreitol (methanol/DMF, RT, 90 min) resulting in complete reduction of the azides to primary amines, which were subsequently acylated with two different acyl chlorides. Products were characterized by 1H NMR, 19F NMR, and FT-IR spectroscopies, and size exclusion chromatography. Given their adaptability, perfluorophenylazides have large potential as multi-purpose intermediates in polymer and materials chemistry.
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Azide–para-Fluoro Substitution on Polymers: Multipurpose Precursors for Efficient Sequential Postpolymerization Modification
2019Co-Authors: Janina-miriam Noy, Willi Smolan, Peter J. RothAbstract:The 2,3,4,5,6-pentafluorobenzyl group has become a popular reactive functionality in polymer chemistry because of its high susceptibility to para-fluoro substitution with thiols. Herein, it is demonstrated postpolymerization that the para-fluoride can be substituted using sodium azide and that the resulting 4-azido-2,3,5,6-tetrafluorobenzyl-functional polymers are versatile precursors for a multitude of onward modifications with click-like efficiencies. Quantitative azide–para-fluoro substitution was found for poly(2,3,4,5,6-pentafluorobenzyl methacrylate) and the related Passerini ester–amide (meth)acrylic (co)polymers when heated in DMF with sodium azide to 80 °C for 60–90 min. Conversely, the azidation of poly(2,3,4,5,6-pentafluorostyrene) under similar conditions resulted in ∼90% substitution efficiency. Azide-functional (co-)polymers were thermally stable below 100 °C and were subsequently modified with (i) four different alkynes (CuBr, triethylamine, DMF, 55 °C, overnight) to give 1,4-substituted 1,2,3-triazoles in >95% conversions; (ii) potassium thioacetate (DMF, RT, 15 min) with quantitative amidation to the Acetanilide Derivative; and (iii) dl-dithiothreitol (methanol/DMF, RT, 90 min), resulting in complete reduction of the azides to primary amines, which were subsequently acylated with two different acyl chlorides. Products were characterized by 1H NMR, 19F NMR, Fourier transform infrared spectroscopies, and size exclusion chromatography. Given their adaptability, perfluorophenylazides have huge potential as multipurpose intermediates in polymer and materials chemistry
Mukesh Patel - One of the best experts on this subject based on the ideXlab platform.
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Investigation of structure–activity relationships for mitochondrial toxicity
Toxicology Letters, 2010Co-Authors: L. Fisk, N. Greene, Russell T. Naven, Mukesh PatelAbstract:Adverse reactions leading to the withdrawal of therapeutic drugs from the market are a serious issue for pharmaceutical companies Chemically-induced mitochondrial 1 Lhasa Limited, 22-23 Blenheim Terrace, Woodhouse Lane, Leeds LS2 9HD, UK 2 Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Pfizer Inc, Groton, CT 05340, USA Lilia.Fisk@lhasalimited.org . dysfunction has been identified as one of the mechanisms which may contribute to a variety of effects such as hepatotoxicity, nephrotoxicity and cardiotoxicity. These effects are difficult to detect in current in vivo studies, and therefore may not be seen prior to the drug reaching a significant patient population. In silico prediction of toxicity based on chemical structure is one of a number of methods that can be applied at the early stages of the drug development cycle to identify potential liabilities. Structure-activity relationships (SARs) derived from publicly available data and implemented as structural alerts and rapid prototype alerts have been applied to the prediction of toxicity for a number of endpoints including hepatotoxicity and cardiotoxicity. This work investigates chemical classes causing mitochondrial toxicity and their implementation as rapid prototype alerts. A database of chemical structures was constructed for 105 compounds reported to cause mitochondrial dysfunction by O’Brien and colleagues1. The compounds were processed against a knowledge base of structural alerts which have been implemented in the Derek for Windows (DfW) expert system (version 12)2. 81 Compounds activated existing alerts and rapid prototype alerts for hepatotoxicity and cardiotoxicity. These were considered as positive predictions for a mitochondrial effect. The compounds that were not predicted by these alerts were then visually analysed and 8 further classes were identified as potential candidates for development as rapid prototype alerts for mitochondrial dysfunction and are currently being implemented. In addition for each rapid prototype alert further literature investigation is being carried out to add supporting data. Examples of SARs developed include biguanide Derivatives and phenol containing compounds. Introduction An expert system approach involves the analysis and interpretation of chemical and toxicological data to identify SARs, followed by their implementation as structural alerts. In this work the method was applied for developing structural alerts for the prediction of mitochondrial dysfunction, that can be used for screening new drug candidates at the early stages of drug development. Mitochondrial dysfunction is thought to be a potential mechanism leading to toxic effects in the liver and heart. Structural alerts which are predictive of hepatotoxicity and cardiotoxicity may indirectly also indicate mitochondrial damage. Here we investigated the coverage of these existing alerts to predict for mitochondrial dysfunction and to identify potential new classes. Materials and methods The data set of 105 compounds for mitochondrial toxicity was constructed based on their reported mitochondrial liability as described by O’Brien and colleagues1. All compounds in this data set were positive. The data set was processed in DfW against alerts for hepatotoxicity, cardiotoxicity and related endpoints. The false negatives were then analysed visually to identify new potential classes. The published literature was additionally investigated to determine if further supporting data (compounds with similar toxic effects and mechanism of toxicity) was available for each class. The methodology for developing these new prototype alerts is summarised in figure 1. Extraction of toxicity data and construction of data set Identification of candidate classes Analysis of data set Figure 1. The alert development process. Results Research and expert analysis SAR development and implementation of new prototype alert 1. Current predictions and new candidate classes The following endpoints were included in the analysis: hepatotoxicity, cardiotoxicity (including HERG channel inhibition), phospholipidosis and rapid prototype alerts for hepatotoxicity and bradycardia. 81 Compounds activating alerts for the above endpoints were considered as correctly predicted giving a sensitivity score for this data set of 77.1%. The remaining 24 false negatives were visually analysed and 8 classes were identified as potential candidates for mitochondrial toxicity alerts (table 1). Biguanide Derivative Based on the available published literature, the mechanism of toxicity for biguanides suggests the inhibition of complex 1 and disruption of the electron transport chain, and as consequence, reduction of ATP production. Increased consumption of glucose and the build-up of pyruvate leads to lactic acidosis, a recognised side effect of this class3. Examples used to derive the SAR and the prototype alert are shown in figure 2. Class no Class name Number of false negatives b f i tf i h f i N N H NH NH2 NH N H N H NH NH2 NH N H N H NH NH2 NH A B Phenol Two compounds from the data set (pentachlorophenol and propofol) were the starting point for this class. Literature research provided additional examples (butylated hydroxytoluene (BHT) and hexachlorophene) supporting mitochondrial dysfunction of phenols (figure 3). The mechanism of mitochondrial toxicity for phenols is related to their ability to act as uncouplers of oxidative phosphorylation4. In-house data suggest that halogenated phenols are much stronger in their uncoupling activity then alkylated phenols. 1 Biguanide Derivative 3 2 Amino-Acetanilide Derivative 2 3 Tropolone Derivative 2 4 Phenol 2 5 Benzamidine Derivative 1 6 1,4-Benzoquinone Derivative 1 7 Quaternary ammonium cation 1 8 Nitrogen mustard 1 u orm n me orm n p en orm n Figure 2. A example of biguanides used for SAR, B – prototype alert.
Sergey P Verevkin - One of the best experts on this subject based on the ideXlab platform.
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Solubility predictions of Acetanilide Derivatives in water: Combining thermochemistry and thermodynamic modeling
Fluid Phase Equilibria, 2018Co-Authors: Christoph Held, Joscha Brinkmann, Anna-dorina Schröder, Mikhail I. Yagofarov, Sergey P VerevkinAbstract:Abstract Knowledge about solubility in water is required for crystallization processes, for the development of structure-property relationships, for the establishment of solubility scales, assessing environmental contamination, and for validating thermodynamic models. Approaches are desired that allow predicting solubility without the use of any experimental solubility data. Most methods that have been proposed to predict aqueous solubility of organic compounds face low prediction reliability and the lack of model interpretability. This work proposes the use of a thermodynamic approach for the prediction of solubility of Acetanilide and its Derivatives in water. This approach requires fusion enthalpy and fusion temperature as well as the activity coefficient of the respective Acetanilide Derivative. The latter was obtained by the equation of state PC-SAFT, which uses thermochemistry data as input for model parametrization. The thermochemical data on Acetanilide and its Derivatives (vapor and sublimation pressures, sublimation and fusion enthalpies) were collected from the literature and evaluated for internal consistency. In order to validate the final solubility prediction model, aqueous solubility of Acetanilide and 17 Derivatives were predicted and compared to experimental solubility data from literature at 298.15 K as well as to an ideal solubility model, which assumes ideal mixture behavior. The results showed that mixtures of Acetanilides + water are highly non-ideal, and the average deviations between solubility data and ideal solubility model could be reduced by two orders of magnitude by using PC-SAFT for the solubility predictions. More promising, PC-SAFT was found to allow predicting the temperature dependence of the aqueous solubility accurately, while ideal solubility model failed to quantitatively describe temperature-dependent solubility.
