The Experts below are selected from a list of 1008 Experts worldwide ranked by ideXlab platform
David Sulzer - One of the best experts on this subject based on the ideXlab platform.
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Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons
ACS chemical neuroscience, 2018Co-Authors: Adam Henke, Yekaterina Kovalyova, Matthew Dunn, Dominik Dreier, Niko G. Gubernator, Iva Dincheva, Christopher Hwu, Peter Šebej, Mark S. Ansorge, David SulzerAbstract:Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the Acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure–activity study revealed the basic structural chemotype of aminoalkyl Acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SE...
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Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons
2017Co-Authors: Adam Henke, Yekaterina Kovalyova, Matthew Dunn, Dominik Dreier, Niko G. Gubernator, Iva Dincheva, Christopher Hwu, Mark S. Ansorge, Peter Šebej, David SulzerAbstract:Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the Acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure–activity study revealed the basic structural chemotype of aminoalkyl Acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers
Ikuro Abe - One of the best experts on this subject based on the ideXlab platform.
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cloning expression and functional identification of a type iii polyketide synthase gene from huperzia serrata
Acta pharmaceutica Sinica, 2011Co-Authors: Ping Zhang, Ikuro Abe, Jieyin Sun, Guoshen Chen, Chaotan Guo, Hiroshi NoguchiAbstract:A cDNA encoding novel type III polyketide synthase (PKS) was cloned and sequenced from young leaves of Chinese club moss Huperzia serrata (Thunb.) Trev. by RT-PCR using degenerated primers based on the conserved sequences of known CHSs, and named as H. serrata PKS2. The terminal sequences of cDNA were obtained by the 3'- and 5'-RACE method. The full-length cDNA of H. serrata PKS2 contained a 1212 bp open reading frame encoding a 46.4 kDa protein with 404 amino acids. The deduced amino acid sequence of H. serrata PKS2 showed 50%-66% identities to those of other chalcone synthase super family enzymes of plant origin. The recombinant H. serrata PKS2 was functionally expressed in Escherichia coli with an additional hexahistidine tag at the N-terminus and showed unusually versatile catalytic potency to produce various aromatic tetraketides, including chalcones, benzophenones, phloroglucinols, and Acridones. In particular, the enzyme accepted bulky starter substrates N-methylanthraniloyl-CoA, and carried out three condensations with malonyl-CoA to produce 1, 3-dihydroxy-N-methylAcridone. Interestingly, H. serrata PKS2 lacks most of the consensus active site sequences with Acridone synthase from Ruta graveolens (Rutaceae).
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An Acridone-producing novel multifunctional type III polyketide synthase from Huperzia serrata.
The FEBS journal, 2007Co-Authors: Kiyofumi Wanibuchi, Hiroyuki Morita, Hiroshi Noguchi, Toshiyuki Kohno, Guoshen Chen, Ping Zhang, Tsuyoshi Abe, Ikuro AbeAbstract:A cDNA encoding a novel plant type III polyketide synthase was cloned and sequenced from the Chinese club moss Huperzia serrata (Huperziaceae). The deduced amino acid sequence of Hu. serrata polyketide synthase 1 showed 44–66% identity to those of other chalcone synthase superfamily enzymes of plant origin. Further, phylogenetic tree analysis revealed that Hu. serrata polyketide synthase 1 groups with other nonchalcone-producing type III polyketide synthases. Indeed, a recombinant enzyme expressed in Escherichia coli showed unusually versatile catalytic potential to produce various aromatic tetraketides, including chalcones, benzophenones, phloroglucinols, and Acridones. In particular, it is remarkable that the enzyme accepted bulky starter substrates such as 4-methoxycinnamoyl-CoA and N-methylanthraniloyl-CoA, and carried out three condensations with malonyl-CoA to produce 4-methoxy-2′,4′,6′-trihydroxychalcone and 1,3-dihydroxy-N-methylAcridone, respectively. In contrast, regular chalcone synthase does not accept these bulky substrates, suggesting that the enzyme has a larger starter substrate-binding pocket at the active site. Although Acridone alkaloids have not been isolated from Hu. serrata, this is the first demonstration of the enzymatic production of Acridone by a type III polyketide synthase from a non-Rutaceae plant. Interestingly, Hu. serrata polyketide synthase 1 lacks most of the consensus active site sequences with Acridone synthase from Ruta graveolens (Rutaceae).
Adam Henke - One of the best experts on this subject based on the ideXlab platform.
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Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons
ACS chemical neuroscience, 2018Co-Authors: Adam Henke, Yekaterina Kovalyova, Matthew Dunn, Dominik Dreier, Niko G. Gubernator, Iva Dincheva, Christopher Hwu, Peter Šebej, Mark S. Ansorge, David SulzerAbstract:Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the Acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure–activity study revealed the basic structural chemotype of aminoalkyl Acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SE...
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Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons
2017Co-Authors: Adam Henke, Yekaterina Kovalyova, Matthew Dunn, Dominik Dreier, Niko G. Gubernator, Iva Dincheva, Christopher Hwu, Mark S. Ansorge, Peter Šebej, David SulzerAbstract:Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the Acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure–activity study revealed the basic structural chemotype of aminoalkyl Acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers
Krystyna Dzierzbicka - One of the best experts on this subject based on the ideXlab platform.
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recent developments in the synthesis and biological activity of acridine Acridone analogues
RSC Advances, 2017Co-Authors: Monika Gensickakowalewska, Grzegorz Cholewiński, Krystyna DzierzbickaAbstract:Many people in the world struggle with cancer or bacterial, parasitic, viral, Alzheimer's and other diseases. Therefore, many scientists seek new, more effective, more selective and less toxic drugs. Acridine/Acridone derivatives constitute a class of compounds with a broad spectrum of biological activity and are of great interest to scientists. To date, many acridine/Acridone analogues have been obtained, which, inter alia, exhibit antitumour (e.g., (1–5)), antimicrobial (e.g., (59)), and antiviral (e.g., (61)) activities and are applicable in the treatment of Alzheimer's disease (e.g., (26)). However, in many cases, their clinical application is limited and excluded because of side effects. In this survey, we describe acridine and Acridone derivatives reported since 2013, methods of their synthesis and their potential clinical applications.
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Synthesis and biological activity of ester derivatives of mycophenolic acid and acridines/Acridones as potential immunosuppressive agents
2015Co-Authors: Grzegorz Cholewiński, Dorota Iwaszkiewicz-grzes, Piotr Trzonkowski, Krystyna DzierzbickaAbstract:Improved derivatives of mycophenolic acid (MPA) are necessary to reduce the frequency of adverse effects, this drug exerts in treated patients. In this study, MPA was coupled with N-(ω-hydroxyalkyl)-9-Acridone-4-carboxamides or N-(ω-hydroxyalkyl)acridine-4-carboxamides to give respective ester conjugates upon Yamaguchi protocol. This esterification required protection of phenol group in MPA. Designed conjugates revealed higher potency in vitro than parent MPA. Acridine derivatives were more active than Acridone analogs and length of the alkyl linker between MPA and heterocyclic units influenced the observed cytotoxicity. Derivatives 2b, 2d, 3a, 3b displayed the most promising immunosuppressive activity.
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synthesis and biological activity of novel mycophenolic acid conjugates containing nitro acridine Acridone derivatives
European Journal of Medicinal Chemistry, 2012Co-Authors: Magdalena Malachowskaugarte, Grzegorz Cholewiński, Krystyna Dzierzbicka, Piotr TrzonkowskiAbstract:Abstract Hybrid pharmacophore anti-proliferative compounds, comprised of mycophenolic acid (MPA) and 1-nitroacridine/4-nitroAcridone derivative have been synthesized and evaluated as inhibitors of five different leukemia cell lines (Jurkat, Molt-4, HL-60, CCRF-CEM, L1210) and human peripheral blood mononuclear cells from healthy donors. These conjugates possess different length of the linker between MPA and heterocyclic units. The type of heterocyclic part influenced their cytotoxic and anti-proliferative properties. Coupling of MPA 1 with 9-(ω-aminoalkyl)amino-1-nitroacridines 2 and 1-[(ω-aminoalkyl)-4-nitro-9(10 H )]-Acridones 3 was tested. Although all tested conjugates were active, compounds 4a – e exhibited the highest potency. Preliminary experiments with GMP suggested that the tested compounds acted as IMPDH inhibitors.
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natural and synthetic acridines Acridones as antitumor agents their biological activities and methods of synthesis
ChemInform, 2012Co-Authors: Grzegorz Cholewiński, Krystyna Dzierzbicka, Aleksander M KolodziejczykAbstract:Acridine derivatives constitute a class of compounds that are being intensively studied as potential anticancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is limited or even excluded because of side effects. Numerous synthetic methods are focused on the preparation of target acridine skeletons or modifications of naturally occurring compounds, such as Acridone alkaloids, that exhibit promising anticancer activities. They have been examined in vitro and in vivo to test their importance for cancer treatment and to establish the mechanism of action at both the molecular and cellular level, which is necessary for the optimization of their properties so that they are suitable in chemotherapy. In this article, we review natural and synthetic acridine/Acridone analogs, their application as anticancer drugs and methods for their preparation.
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synthesis and antitumor activity of conjugates of muramyldipeptide or normuramyldipeptide with hydroxyacridine Acridone derivatives
Journal of Medicinal Chemistry, 2003Co-Authors: Krystyna Dzierzbicka, Aleksander KolodziejczykAbstract:A series of MDP (muramyldipeptide) or nor-MDP (normuramyldipeptide) analogues modified at the C-terminus post of the molecule by a formation of an ester bond between the carboxylic group of isoglutamine and the hydroxyl function of the respective derivatives of 4-carboxamide-acridine/9-Acridone or 1-nitro-9-hydroxyalkylaminoacridines were synthesized as potential anticancer agents. The compounds O-(1-O-benzyl-N-acetyl-muramyl-l-alanyl-d-γ-isoglutaminyl)-9-(ethylamino)-1-nitroacridine ester 3j and O-(1-O-benzyl-N-acetyl-muramyl-l-alanyl-d-γ-isoglutaminyl)-9-propylamino-1-nitroacridine ester 3k exhibited high in vitro cytotoxic activity against a panel of human cell lines, prostate cancer and AIDS-related lymphoma (ARL). Analogue 3j was also active in vivo in the hollow fiber assay. Antitumor activity of both compounds were tested in vivo against difference human tumor xenograft, but only analogue 3k showed in vivo activity against sc UACC-62 melanoma in mice.
Hiroshi Noguchi - One of the best experts on this subject based on the ideXlab platform.
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cloning expression and functional identification of a type iii polyketide synthase gene from huperzia serrata
Acta pharmaceutica Sinica, 2011Co-Authors: Ping Zhang, Ikuro Abe, Jieyin Sun, Guoshen Chen, Chaotan Guo, Hiroshi NoguchiAbstract:A cDNA encoding novel type III polyketide synthase (PKS) was cloned and sequenced from young leaves of Chinese club moss Huperzia serrata (Thunb.) Trev. by RT-PCR using degenerated primers based on the conserved sequences of known CHSs, and named as H. serrata PKS2. The terminal sequences of cDNA were obtained by the 3'- and 5'-RACE method. The full-length cDNA of H. serrata PKS2 contained a 1212 bp open reading frame encoding a 46.4 kDa protein with 404 amino acids. The deduced amino acid sequence of H. serrata PKS2 showed 50%-66% identities to those of other chalcone synthase super family enzymes of plant origin. The recombinant H. serrata PKS2 was functionally expressed in Escherichia coli with an additional hexahistidine tag at the N-terminus and showed unusually versatile catalytic potency to produce various aromatic tetraketides, including chalcones, benzophenones, phloroglucinols, and Acridones. In particular, the enzyme accepted bulky starter substrates N-methylanthraniloyl-CoA, and carried out three condensations with malonyl-CoA to produce 1, 3-dihydroxy-N-methylAcridone. Interestingly, H. serrata PKS2 lacks most of the consensus active site sequences with Acridone synthase from Ruta graveolens (Rutaceae).
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An Acridone-producing novel multifunctional type III polyketide synthase from Huperzia serrata.
The FEBS journal, 2007Co-Authors: Kiyofumi Wanibuchi, Hiroyuki Morita, Hiroshi Noguchi, Toshiyuki Kohno, Guoshen Chen, Ping Zhang, Tsuyoshi Abe, Ikuro AbeAbstract:A cDNA encoding a novel plant type III polyketide synthase was cloned and sequenced from the Chinese club moss Huperzia serrata (Huperziaceae). The deduced amino acid sequence of Hu. serrata polyketide synthase 1 showed 44–66% identity to those of other chalcone synthase superfamily enzymes of plant origin. Further, phylogenetic tree analysis revealed that Hu. serrata polyketide synthase 1 groups with other nonchalcone-producing type III polyketide synthases. Indeed, a recombinant enzyme expressed in Escherichia coli showed unusually versatile catalytic potential to produce various aromatic tetraketides, including chalcones, benzophenones, phloroglucinols, and Acridones. In particular, it is remarkable that the enzyme accepted bulky starter substrates such as 4-methoxycinnamoyl-CoA and N-methylanthraniloyl-CoA, and carried out three condensations with malonyl-CoA to produce 4-methoxy-2′,4′,6′-trihydroxychalcone and 1,3-dihydroxy-N-methylAcridone, respectively. In contrast, regular chalcone synthase does not accept these bulky substrates, suggesting that the enzyme has a larger starter substrate-binding pocket at the active site. Although Acridone alkaloids have not been isolated from Hu. serrata, this is the first demonstration of the enzymatic production of Acridone by a type III polyketide synthase from a non-Rutaceae plant. Interestingly, Hu. serrata polyketide synthase 1 lacks most of the consensus active site sequences with Acridone synthase from Ruta graveolens (Rutaceae).
