The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Xiaojun Yao - One of the best experts on this subject based on the ideXlab platform.
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an Aporphine Alkaloid from nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure activity correlations
Natural Product Research, 2012Co-Authors: Zhongduo Yang, Xu Zhang, Feng Guo, Xiaojun YaoAbstract:N-methylasimilobine (1), a new-found strong acetylcholinesterase (AChE) inhibitor, along with two weakly active Aporphine Alkaloids, nuciferine (2) and nornuciferine (3) were separated from Nelumbo nucifera. N-methylasimilobine (1) inhibited 50% of AChE activity at the concentrations of 1.5 ± 0.2 µg mL−1 when the standard IC50 value of Physostigmine was 0.013 ± 0.002 µg mL−1. The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE.
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An Aporphine Alkaloid from Nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure–activity correlations
Natural product research, 2011Co-Authors: Zhongduo Yang, Xu Zhang, Feng Guo, Xiaojun YaoAbstract:N-methylasimilobine (1), a new-found strong acetylcholinesterase (AChE) inhibitor, along with two weakly active Aporphine Alkaloids, nuciferine (2) and nornuciferine (3) were separated from Nelumbo nucifera. N-methylasimilobine (1) inhibited 50% of AChE activity at the concentrations of 1.5 ± 0.2 µg mL−1 when the standard IC50 value of Physostigmine was 0.013 ± 0.002 µg mL−1. The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE.
Bruce K. Cassels - One of the best experts on this subject based on the ideXlab platform.
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Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine
International journal of molecular sciences, 2018Co-Authors: Sakineh Kazemi Noureini, Mitra Kheirabadi, Fatima Masoumi, Farve Khosrogerdi, Younes Zarei, Cristian Suárez-rozas, Julio Salas-norambuena, Bruce K. CasselsAbstract:Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant Aporphine Alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum, was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC50 value of about 0.17 ± 0.1 µM for BSB, roughly 400 times stronger than boldine, while the LD50 in the cytotoxicity assays were 12.5 and 21.88 µM, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC50 for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations.
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structure affinity relationships of halogenated predicentrine and glaucine derivatives at d1 and d2 dopaminergic receptors halogenation and d1 receptor selectivity
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Marcelo Asencio, Claudio Hurtadoguzman, John J Lopez, Philippe Protais, Bruce K. Cassels, Abdeslam ChagraouiAbstract:Abstract Halogenation of the Aporphine Alkaloid boldine at the 3-position leads to increased affinity for rat brain D 1 -like dopaminergic receptors with some selectivity over D 2 -like receptors. A series of 3-halogenated and 3,8-dihalogenated (halogen = Cl, Br or I) derivatives of predicentrine (9- O -methylboldine) and glaucine (2,9-di- O -methylboldine) were prepared and assayed for binding at D 1 and D 2 sites. Halogenation of predicentrine led to strong increases in affinity for D 1 -like receptors, while the affinities for D 2 -like receptors were either practically unchanged or reduced three- to fourfold. Halogenated glaucine derivatives did not show any clear trend towards enhanced selectivity, and the affinities were poor and similar to or worse than the values previously recorded for glaucine itself. Together with earlier work on boldine derivatives, these results suggest that the 2-hydroxy group on the Aporphine skeleton may determine a binding mode favoring D 1 -like over D 2 -like receptors, with enhanced affinity when the C-3 position is halogenated.
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NEW HETEROCYCLIC SKELETONS DERIVED FROM THE Aporphine Alkaloid BOLDINE
Synthetic Communications, 2002Co-Authors: Eduardo Sobarzo-sánchez, Bruce K. Cassels, Carolina Jullian, Claudio SaitzAbstract:ABSTRACT The abundant Aporphine Alkaloid (S)-(+)-boldine (1) was selectively nitrosated with sodium nitrite in acetic acid affording 8-nitrosoboldine (2) which was hydrogenated catalytically to give 8-aminoboldine (3). The latter was used as the starting material for annulations with ethyl ortho-formate to afford the corresponding oxazole (“boldine-9,8-oxazole”, 4), and with methyl benzoylformate giving the phenyl-oxazinone (“boldine-9,8-phenyloxazinone”, 5). This later product was treated with KOH/EtOH at room temperature and converted quickly into the ring-contracted phenyloxazole (“boldine-9,8-phenyloxazole”, 6) in moderate yield.
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Cytoprotective and antioxidant effects of boldine on tert-butyl hydroperoxide—induced damage to isolated hepatocytes
Cell Biology and Toxicology, 1996Co-Authors: R. Bannach, Bruce K. Cassels, A. Valenzuela, L. J. Núnez-vergara, H. SpeiskyAbstract:Boldine, an Aporphine Alkaloid, was recently shown by us to exhibit potent antioxidant properties. We report here that boldine concentration-dependently inhibited the peroxidative (accumulation of thiobarbituric acid reactive substances) and lytic damage (trypan blue exclusion and lactate dehydrogenase leakage) to isolated rat hepatocytes induced by tert -butyl hydroperoxide (TBOOH). Boldine (200 μmol/L) fully cytoprotected and completely prevented the peroxidation induced by TBOOH a concentrations equal to or lower than 0.87 mmol/L. However, at a peroxide concentration of 0.91 mmol/L, although boldine completely inhibited lipid peroxidation it largely failed to afford cytoprotection against TBOOH. TBOOH alone (0.83 mmol/L) caused an early (within 60 s) sudden decline of reduced glutathione (by 50%) and an equivalent increase in the levels of oxidized glutathione. Neither of these effects was prevented by the simultaneous addition of a cytoprotective and antioxidant concentration of boldine (200 μmol/L). The delayed addition of boldine to the suspension (after 10 or 20 min), while effectively blocking any further increase in thiobarbituric acid reactive substances, totally failed to prevent the peroxide-induced loss in cell viability. Conversely, preincubation of the hepatocytes with boldine for 150 min (at which time no boldine could be detected in either intra- or extracellular spaces) prevented lipid peroxidation and was as effective in protecting the cells against the damage caused by the subsequent addition of TBOOH as the simultaneous addition of boldine and TBOOH to hepatocytes preincubated for 150 min under control conditions.
Sakineh Kazemi Noureini - One of the best experts on this subject based on the ideXlab platform.
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Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine
International journal of molecular sciences, 2018Co-Authors: Sakineh Kazemi Noureini, Mitra Kheirabadi, Fatima Masoumi, Farve Khosrogerdi, Younes Zarei, Cristian Suárez-rozas, Julio Salas-norambuena, Bruce K. CasselsAbstract:Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant Aporphine Alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum, was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC50 value of about 0.17 ± 0.1 µM for BSB, roughly 400 times stronger than boldine, while the LD50 in the cytotoxicity assays were 12.5 and 21.88 µM, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC50 for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations.
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Boldine, a natural Aporphine Alkaloid, inhibits telomerase at non-toxic concentrations.
Chemico-biological interactions, 2015Co-Authors: Sakineh Kazemi Noureini, Fatemeh TanavarAbstract:In a preliminary screening study of natural Alkaloids, boldine, an Aporphine Alkaloid, showed an interesting dose and time dependent anti-proliferative effect in several cancer cell lines. Cytotoxicity of boldine in human fibroblasts was considerably lower than the telomerase positive embryonic kidney HEK293 and breast cancer MCF-7 and MDA-MB-231 cells. Whether boldine can inhibit telomerase was investigated here using a modified quantitative real-time telomere repeat amplification protocol (q-TRAP). This test showed that boldine inhibits telomerase in cells treated with sub-cytotoxic concentrations. Telomerase inhibition occurs via down-regulation of hTERT, the catalytic subunit of the enzyme. Boldine changed the splicing variants of hTERT towards shorter non-functional transcripts as well. A direct interaction of boldine with the enzyme may also be involved, though thermal FRET method did not detect any substantial interaction between boldine and synthetic telomere sequences. This study advocates boldine as a valuable candidate for telomerase-targeted cancer care. This study suggests that derivatives of boldine could be potent anti-cancer drugs.
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Dose-Dependent Cytotoxic Effects of Boldine in HepG-2 Cells—Telomerase Inhibition and Apoptosis Induction
MDPI AG, 2015Co-Authors: Sakineh Kazemi Noureini, Michael WinkAbstract:Plant metabolites are valuable sources of novel therapeutic compounds. In an anti-telomerase screening study of plant secondary metabolites, the Aporphine Alkaloid boldine (1,10-dimethoxy-2,9-dihydroxyAporphine) exhibited a dose and time dependent cytotoxicity against hepatocarcinoma HepG-2 cells. Here we focus on the modes and mechanisms of the growth-limiting effects of this compound. Telomerase activity and expression level of some related genes were estimated by real-time PCR. Modes of cell death also were examined by microscopic inspection, staining methods and by evaluating the expression level of some critically relevant genes. The growth inhibition was correlated with down-regulation of the catalytic subunit of telomerase (hTERT) gene (p < 0.01) and the corresponding reduction of telomerase activity in sub-cytotoxic concentrations of boldine (p < 0.002). However, various modes of cell death were stimulated, depending on the concentration of boldine. Very low concentrations of boldine over a few passages resulted in an accumulation of senescent cells so that HepG-2 cells lost their immortality. Moreover, boldine induced apoptosis concomitantly with increasing the expression of bax/bcl2 (p < 0.02) and p21 (p < 0.01) genes. Boldine might thus be an interesting candidate as a potential natural compound that suppresses telomerase activity in non-toxic concentrations
Alma Rosa González-esquinca - One of the best experts on this subject based on the ideXlab platform.
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Aporphine Alkaloid contents increase with moderate nitrogen supply in Annona diversifolia Saff. (Annonaceae) seedlings during diurnal periods
Natural product research, 2016Co-Authors: José Agustín Orozco-castillo, Rocío Cruz-ortega, Mariano Martínez-vázquez, Alma Rosa González-esquincaAbstract:AbstractAporphine Alkaloids are secondary metabolites that are obtained in low levels from species of the Annonaceae family. Nitrogen addition may increase the Alkaloid content in plants. However, previous studies published did not consider that nitrogen could change the Alkaloid content throughout the day. We conducted this short-term study to determine the effects of nitrogen applied throughout the diurnal period on the Aporphine Alkaloids via measurements conducted on the roots, stems and leaves of Annona diversifolia seedlings. The 60-day-old seedlings were cultured with the addition of three levels of nitrogen (0, 30 and 60 mM), and Alkaloid extracts were analysed using high-performance liquid chromatography. The highest total Alkaloid content was measured in the treatment with moderate nitrogen supply. Further, the levels of Aporphine Alkaloids changed significantly in the first few hours of the diurnal period. We conclude that Aporphine Alkaloid content increased with moderate nitrogen supply and e...
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Aporphine Alkaloid contents increase with moderate nitrogen supply in Annona diversifolia Saff. (Annonaceae) seedlings during diurnal periods
2016Co-Authors: José Agustín Orozco-castillo, Rocío Cruz-ortega, Mariano Martínez-vázquez, Alma Rosa González-esquincaAbstract:Aporphine Alkaloids are secondary metabolites that are obtained in low levels from species of the Annonaceae family. Nitrogen addition may increase the Alkaloid content in plants. However, previous studies published did not consider that nitrogen could change the Alkaloid content throughout the day. We conducted this short-term study to determine the effects of nitrogen applied throughout the diurnal period on the Aporphine Alkaloids via measurements conducted on the roots, stems and leaves of Annona diversifolia seedlings. The 60-day-old seedlings were cultured with the addition of three levels of nitrogen (0, 30 and 60 mM), and Alkaloid extracts were analysed using high-performance liquid chromatography. The highest total Alkaloid content was measured in the treatment with moderate nitrogen supply. Further, the levels of Aporphine Alkaloids changed significantly in the first few hours of the diurnal period. We conclude that Aporphine Alkaloid content increased with moderate nitrogen supply and exhibited diurnal variation.
Zhongduo Yang - One of the best experts on this subject based on the ideXlab platform.
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an Aporphine Alkaloid from nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure activity correlations
Natural Product Research, 2012Co-Authors: Zhongduo Yang, Xu Zhang, Feng Guo, Xiaojun YaoAbstract:N-methylasimilobine (1), a new-found strong acetylcholinesterase (AChE) inhibitor, along with two weakly active Aporphine Alkaloids, nuciferine (2) and nornuciferine (3) were separated from Nelumbo nucifera. N-methylasimilobine (1) inhibited 50% of AChE activity at the concentrations of 1.5 ± 0.2 µg mL−1 when the standard IC50 value of Physostigmine was 0.013 ± 0.002 µg mL−1. The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE.
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An Aporphine Alkaloid from Nelumbo nucifera as an acetylcholinesterase inhibitor and the primary investigation for structure–activity correlations
Natural product research, 2011Co-Authors: Zhongduo Yang, Xu Zhang, Feng Guo, Xiaojun YaoAbstract:N-methylasimilobine (1), a new-found strong acetylcholinesterase (AChE) inhibitor, along with two weakly active Aporphine Alkaloids, nuciferine (2) and nornuciferine (3) were separated from Nelumbo nucifera. N-methylasimilobine (1) inhibited 50% of AChE activity at the concentrations of 1.5 ± 0.2 µg mL−1 when the standard IC50 value of Physostigmine was 0.013 ± 0.002 µg mL−1. The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE.