The objective of this study was to investigate the pharmacokinetics and pharmacodynamics (anticon... more The objective of this study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of a series of amide derivatives of glycinamide in order to explore their structure pharmacokinetic-pharmacodynamic relationship and to discover a glycinamide derivative which might have the potential to become a new antiepileptic agent. The following compounds were investigated: glycylglycine, glycylglycinamide, gaboylglycinamide, N-acetylglycine, N-acetylglycinamide, N-acetylglycylglycinamide, N-acetyl, N'-benzylglycinamide, N-benzyloxycarbonylglycine or Z-glycine, Z-glycinamide, Z-glycylglycine and Z-glycylglycinamide. The anticonvulsant activity and neurotoxicity study was carried out in classical animal models for anticonvulsant screening. The pharmacokinetics of the active compounds was studied in dogs, which is a common animal model for a comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, all the dipeptides of glycinamide and the glycine derivatives were found to be inactive. The only two active compounds were: N-acetyl,N'-benzylglycinamide (VII) and Z-glycinamide (IX). These compounds demonstrated similar pharmacokinetic profiles. Unlike glycine or glycinamide, compounds VII and IX, being lipophilic derivatives of glycinamide, showed anticonvulsant activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacodynamics and pharmacokinetics of compounds VII and IX were similar to that of the potential new antiepileptics; N-valproylglycinamide and phthaloylglycinamide. This study provides certain clues concerning the structural requirements for the design of anticonvulsant-active glycine derivatives.
Nanomedicine: Nanotechnology, Biology and Medicine, Aug 1, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Plasma cells (PCs) are terminally differentiated B lymphocytes responsible for the synthesis and ... more Plasma cells (PCs) are terminally differentiated B lymphocytes responsible for the synthesis and secretion of Igs. The differentiation of B cells into PCs involves a remarkable expansion of both lipid and protein components of the endoplasmic reticulum. Despite their importance in many signal transduction pathways, the role of ceramides, and of complex sphingolipids that are derived from ceramide, in PC differentiation has never been directly studied. To assess their putative role in PC differentiation, we blocked ceramide synthesis with fumonisin B1, a specific inhibitor of ceramide synthase. Under fumonisin B1 treatment, N-linked glycosylation was severely impaired in LPS-activated, but not in naive, B cells. We also show that ceramide synthesis is strongly induced by XBP-1 (X box-binding protein-1). In the absence of ceramide synthesis, ER expansion was dramatically diminished. Our results underscore ceramide biosynthesis as a key metabolic pathway in the process of PC differentiation and reveal a previously unknown functional link between sphingolipids and N-linked glycosylation in PCs.
Journal of the American Chemical Society, Dec 1, 1976
A Novel Base-Catalyzed Rearrangement. Formation of Di benzo[ cd,gh]pentalenide Dianion Sir: Molec... more A Novel Base-Catalyzed Rearrangement. Formation of Di benzo[ cd,gh]pentalenide Dianion Sir: Molecular rearrangements are of great significance both as synthetic tools and in mechanistic studies. Most rearrangements, especially in the aromatic series, are acid-catalyzed and only a few are base-cata1yzed.l A well-known base-catalyzed rearrangement in the aromatic series is the Smiles rearrangement2 in which a carbanion in a system including a heteroatom is rearranged. For example, a system
In the last paragraph, the text should read as follows: The CMPE had an average of 50 nmol of PE/... more In the last paragraph, the text should read as follows: The CMPE had an average of 50 nmol of PE/mg of carboxymethylcellulose (CMC), Hepa-PE 20 nmol of PE/mg of heparin, and Hyal-PE 25 nmol of PE/mg of hyaluronic acid (Hyal). If the respective polymer molecular weights are taken into account, these correspond to 2.5-5 PE molecules/ CMC molecule in CMPE, 0.6 PE molecule/molecule of heparin in Hepa-PE, and 0.76 PE molecule/molecule of hyaluronic acid in Hyal-PE.
ChemInform Abstract Durch Kondensation von Homo-phthalaldehyd (I) mit Biphenyl-2'2'-bis-triphenyl... more ChemInform Abstract Durch Kondensation von Homo-phthalaldehyd (I) mit Biphenyl-2'2'-bis-triphenylphosphoniumbromid (II) nach Wittig entsteht mit 10% Ausbeute ein Gemisch der beiden cyclischen Diolefine (III) und (IV), die getrennt und mit dem Dimethylsulfinyl-Carbanion (V) in das Anion (VI)übergeführt werden. (IR-, UV-, NMR-Spektren).
ChemInform Abstract Einstündiges Erwärmen einer Lösung des Tribenzocyclooctans (I) in HMPT mit Bu... more ChemInform Abstract Einstündiges Erwärmen einer Lösung des Tribenzocyclooctans (I) in HMPT mit Butyl-Li auf 80 rc C ergibt zunächst das entsprechende Anion, das sich an-schliessend zum Fluorenidanion (II) umlagert und mit feuchtemÄther als Fluoren abgefangen werden kann (Ausbeute 70%). Analog zu (II) entsteht das Dianion (IV) aus dem Hexacyclus (III).
We have previously shown that cell surface proteoglycans protect the cell membrane from the actio... more We have previously shown that cell surface proteoglycans protect the cell membrane from the action of extracellular phospholipase A2 (PLA2) enzymes [Dan, P., Nitzan, D. W., Dagan, A., Ginsburg, I., and Yedgar, S. (1996) FEBS Lett. 383, 75-78]. Cell-impermeable PLA2 inhibitors (ExPLIs) were prepared by linking phosphatidylethanolamine (PE) to polymeric carriers, specifically, carboxymethylcellulose, heparin, or hyaluronic acid. The structure of these inhibitors enables the incorporation of their PE moiety into the membrane while the polymer remains at the membrane surface. In the present study, we show that the ExPLIs are effective inhibitors of the hydrolysis of different phospholipids in biological (Escherichia coli) and model (phospholipid vesicle) membranes, by diverse types of PLA2 enzymes, specifically human recombinant synovial fluid and C. atrox (type II), as well as Naja mocambique and porcine pancreatic (type I) PLA2. It is proposed that the external polymers of the ExPLIs, which are anchored to the membrane by the PE, mimic the naturally occurring cell surface proteoglycans and similarly protect membranes from the action of exogenous PLA2.
Acid ceramidase (N-acylsphingosine amidohydrolase) is the lysosomal enzyme required to hydrolyze ... more Acid ceramidase (N-acylsphingosine amidohydrolase) is the lysosomal enzyme required to hydrolyze the N-acyl linkage between the fatty acid and sphingosine moieties in ceramide. A deficiency of acid ceramidase activity results in the lipid storage disorder, Farber disease. This study reports a new assay method to detect acid ceramidase activity in vitro using Bodipy or lissamine rhodamine-conjugated ceramide (C12 ceramide; dodecanoylsphingosine). Using mouse kidney extracts as the source of acid ceramidase activity, this new method was compared with an assay using radioactive C12 ceramide (N-[ 14 C]-dodecanoylsphingosine) as a substrate. The Bodipy C12 ceramide substrate provided data very similar to those of the radioactive substrate, but under the experimental conditions tested, it was significantly more sensitive. Using Bodipy C12 ceramide, femtomole quantities of the product, Bodipy dodecanoic acid, could be detected, providing an accurate measure of acid ceramidase activity as low as 0.1 pmol/mg protein/h. Acid ceramidase activities in skin fibroblasts and EBVtransformed lymphoblasts from Farber disease patients were around 7.8 and 10% of those in normal cells, respectively, confirming the specificity of this new assay method. Based on these results, we suggest that this fluorescence-based, high-performance liquid chromatographic technique is a reliable, rapid, and highly sensitive method to determine acid ceramidase activity, and that it could be useful wherever the in vitro detection of acid ceramidase activity is of importance.
Background: Photodynamic treatment of red cell concentrate with phthalocyanines and red light ina... more Background: Photodynamic treatment of red cell concentrate with phthalocyanines and red light inactivates lipid-enveloped viruses such as vesicular stomatitis virus and human immunodeficiency virus. This procedure is evaluated for its ability to enhance the viral safety of red cell concentrate for transfusion. It is of interest to study whether photodynamic treatment could also inactivate parasites in blood (e.g., Plasmodium falciparum). Study Design and Methods: Red cells parasitized by /? falciparum were treated with phthalocyanines and red light and then cultured in vitro for 48 hours. The percentage of parasitemia was then estimated by microscopic examination of the red cells. Results: Of the phthalocyanines studied, the one that proved to be the most effective was HOSiPcOSi(CH,),(CH,),N(CH,), (Pc 4). The extent of parasite inactivation increased with light dose and decreased with an increase in hematocrit. At a hematocrit of 60 percent and 2 pM Pc 4, 23 log,,, kill occurred at a light dose of 60 J per cm2. This is a lower dose than is required for 26 log,,, of vesicular stomatitis virus inactivation (90 J/cm*). Conclusion: Photodynamic treatment with Pc 4 could make red cell concentrate not only virally safe for transfusion but also safe with respect to transmitting malaria. Abbreviations: IC,, the concentration that inhibits response by 50 percent: MC 540 = merocyanine 540; Pc 4 =
The objective of this study was to investigate the pharmacokinetics and pharmacodynamics (anticon... more The objective of this study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of a series of amide derivatives of glycinamide in order to explore their structure pharmacokinetic-pharmacodynamic relationship and to discover a glycinamide derivative which might have the potential to become a new antiepileptic agent. The following compounds were investigated: glycylglycine, glycylglycinamide, gaboylglycinamide, N-acetylglycine, N-acetylglycinamide, N-acetylglycylglycinamide, N-acetyl, N'-benzylglycinamide, N-benzyloxycarbonylglycine or Z-glycine, Z-glycinamide, Z-glycylglycine and Z-glycylglycinamide. The anticonvulsant activity and neurotoxicity study was carried out in classical animal models for anticonvulsant screening. The pharmacokinetics of the active compounds was studied in dogs, which is a common animal model for a comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, all the dipeptides of glycinamide and the glycine derivatives were found to be inactive. The only two active compounds were: N-acetyl,N'-benzylglycinamide (VII) and Z-glycinamide (IX). These compounds demonstrated similar pharmacokinetic profiles. Unlike glycine or glycinamide, compounds VII and IX, being lipophilic derivatives of glycinamide, showed anticonvulsant activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacodynamics and pharmacokinetics of compounds VII and IX were similar to that of the potential new antiepileptics; N-valproylglycinamide and phthaloylglycinamide. This study provides certain clues concerning the structural requirements for the design of anticonvulsant-active glycine derivatives.
Nanomedicine: Nanotechnology, Biology and Medicine, Aug 1, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Plasma cells (PCs) are terminally differentiated B lymphocytes responsible for the synthesis and ... more Plasma cells (PCs) are terminally differentiated B lymphocytes responsible for the synthesis and secretion of Igs. The differentiation of B cells into PCs involves a remarkable expansion of both lipid and protein components of the endoplasmic reticulum. Despite their importance in many signal transduction pathways, the role of ceramides, and of complex sphingolipids that are derived from ceramide, in PC differentiation has never been directly studied. To assess their putative role in PC differentiation, we blocked ceramide synthesis with fumonisin B1, a specific inhibitor of ceramide synthase. Under fumonisin B1 treatment, N-linked glycosylation was severely impaired in LPS-activated, but not in naive, B cells. We also show that ceramide synthesis is strongly induced by XBP-1 (X box-binding protein-1). In the absence of ceramide synthesis, ER expansion was dramatically diminished. Our results underscore ceramide biosynthesis as a key metabolic pathway in the process of PC differentiation and reveal a previously unknown functional link between sphingolipids and N-linked glycosylation in PCs.
Journal of the American Chemical Society, Dec 1, 1976
A Novel Base-Catalyzed Rearrangement. Formation of Di benzo[ cd,gh]pentalenide Dianion Sir: Molec... more A Novel Base-Catalyzed Rearrangement. Formation of Di benzo[ cd,gh]pentalenide Dianion Sir: Molecular rearrangements are of great significance both as synthetic tools and in mechanistic studies. Most rearrangements, especially in the aromatic series, are acid-catalyzed and only a few are base-cata1yzed.l A well-known base-catalyzed rearrangement in the aromatic series is the Smiles rearrangement2 in which a carbanion in a system including a heteroatom is rearranged. For example, a system
In the last paragraph, the text should read as follows: The CMPE had an average of 50 nmol of PE/... more In the last paragraph, the text should read as follows: The CMPE had an average of 50 nmol of PE/mg of carboxymethylcellulose (CMC), Hepa-PE 20 nmol of PE/mg of heparin, and Hyal-PE 25 nmol of PE/mg of hyaluronic acid (Hyal). If the respective polymer molecular weights are taken into account, these correspond to 2.5-5 PE molecules/ CMC molecule in CMPE, 0.6 PE molecule/molecule of heparin in Hepa-PE, and 0.76 PE molecule/molecule of hyaluronic acid in Hyal-PE.
ChemInform Abstract Durch Kondensation von Homo-phthalaldehyd (I) mit Biphenyl-2'2'-bis-triphenyl... more ChemInform Abstract Durch Kondensation von Homo-phthalaldehyd (I) mit Biphenyl-2'2'-bis-triphenylphosphoniumbromid (II) nach Wittig entsteht mit 10% Ausbeute ein Gemisch der beiden cyclischen Diolefine (III) und (IV), die getrennt und mit dem Dimethylsulfinyl-Carbanion (V) in das Anion (VI)übergeführt werden. (IR-, UV-, NMR-Spektren).
ChemInform Abstract Einstündiges Erwärmen einer Lösung des Tribenzocyclooctans (I) in HMPT mit Bu... more ChemInform Abstract Einstündiges Erwärmen einer Lösung des Tribenzocyclooctans (I) in HMPT mit Butyl-Li auf 80 rc C ergibt zunächst das entsprechende Anion, das sich an-schliessend zum Fluorenidanion (II) umlagert und mit feuchtemÄther als Fluoren abgefangen werden kann (Ausbeute 70%). Analog zu (II) entsteht das Dianion (IV) aus dem Hexacyclus (III).
We have previously shown that cell surface proteoglycans protect the cell membrane from the actio... more We have previously shown that cell surface proteoglycans protect the cell membrane from the action of extracellular phospholipase A2 (PLA2) enzymes [Dan, P., Nitzan, D. W., Dagan, A., Ginsburg, I., and Yedgar, S. (1996) FEBS Lett. 383, 75-78]. Cell-impermeable PLA2 inhibitors (ExPLIs) were prepared by linking phosphatidylethanolamine (PE) to polymeric carriers, specifically, carboxymethylcellulose, heparin, or hyaluronic acid. The structure of these inhibitors enables the incorporation of their PE moiety into the membrane while the polymer remains at the membrane surface. In the present study, we show that the ExPLIs are effective inhibitors of the hydrolysis of different phospholipids in biological (Escherichia coli) and model (phospholipid vesicle) membranes, by diverse types of PLA2 enzymes, specifically human recombinant synovial fluid and C. atrox (type II), as well as Naja mocambique and porcine pancreatic (type I) PLA2. It is proposed that the external polymers of the ExPLIs, which are anchored to the membrane by the PE, mimic the naturally occurring cell surface proteoglycans and similarly protect membranes from the action of exogenous PLA2.
Acid ceramidase (N-acylsphingosine amidohydrolase) is the lysosomal enzyme required to hydrolyze ... more Acid ceramidase (N-acylsphingosine amidohydrolase) is the lysosomal enzyme required to hydrolyze the N-acyl linkage between the fatty acid and sphingosine moieties in ceramide. A deficiency of acid ceramidase activity results in the lipid storage disorder, Farber disease. This study reports a new assay method to detect acid ceramidase activity in vitro using Bodipy or lissamine rhodamine-conjugated ceramide (C12 ceramide; dodecanoylsphingosine). Using mouse kidney extracts as the source of acid ceramidase activity, this new method was compared with an assay using radioactive C12 ceramide (N-[ 14 C]-dodecanoylsphingosine) as a substrate. The Bodipy C12 ceramide substrate provided data very similar to those of the radioactive substrate, but under the experimental conditions tested, it was significantly more sensitive. Using Bodipy C12 ceramide, femtomole quantities of the product, Bodipy dodecanoic acid, could be detected, providing an accurate measure of acid ceramidase activity as low as 0.1 pmol/mg protein/h. Acid ceramidase activities in skin fibroblasts and EBVtransformed lymphoblasts from Farber disease patients were around 7.8 and 10% of those in normal cells, respectively, confirming the specificity of this new assay method. Based on these results, we suggest that this fluorescence-based, high-performance liquid chromatographic technique is a reliable, rapid, and highly sensitive method to determine acid ceramidase activity, and that it could be useful wherever the in vitro detection of acid ceramidase activity is of importance.
Background: Photodynamic treatment of red cell concentrate with phthalocyanines and red light ina... more Background: Photodynamic treatment of red cell concentrate with phthalocyanines and red light inactivates lipid-enveloped viruses such as vesicular stomatitis virus and human immunodeficiency virus. This procedure is evaluated for its ability to enhance the viral safety of red cell concentrate for transfusion. It is of interest to study whether photodynamic treatment could also inactivate parasites in blood (e.g., Plasmodium falciparum). Study Design and Methods: Red cells parasitized by /? falciparum were treated with phthalocyanines and red light and then cultured in vitro for 48 hours. The percentage of parasitemia was then estimated by microscopic examination of the red cells. Results: Of the phthalocyanines studied, the one that proved to be the most effective was HOSiPcOSi(CH,),(CH,),N(CH,), (Pc 4). The extent of parasite inactivation increased with light dose and decreased with an increase in hematocrit. At a hematocrit of 60 percent and 2 pM Pc 4, 23 log,,, kill occurred at a light dose of 60 J per cm2. This is a lower dose than is required for 26 log,,, of vesicular stomatitis virus inactivation (90 J/cm*). Conclusion: Photodynamic treatment with Pc 4 could make red cell concentrate not only virally safe for transfusion but also safe with respect to transmitting malaria. Abbreviations: IC,, the concentration that inhibits response by 50 percent: MC 540 = merocyanine 540; Pc 4 =
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