The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Mark M Moasser - One of the best experts on this subject based on the ideXlab platform.
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s phase inhibition of cell cycle progression by a novel class of Pyridopyrimidine tyrosine kinase inhibitors
Cell Cycle, 2004Co-Authors: Olga A Mizenina, Mark M MoasserAbstract:Increased activity of the src family of oncogenic tyrosine kinases is seen in many human tumors and pharmacologic inhibitors of these kinases are investigated as potential anti-tumor agents. A family of pyrido [2, 3-d] pyrimidine compounds (PD) has been characterized as selective inhibitors of Src kinases. We studied the effects of this class of compounds on cancer cell lines and found that they were highly specific inhibitors of cell cycle progression. These compounds inhibit cells either in the mitotic phase or in mid S-phase; these two activities are mutually exclusive: no compound exerts both activities. We undertook experiments to determine the mechanistic basis for these differences and found additional biochemical activities associated with the S-phase inhibitors. Treatment of cells with the S-phase blocker PD179483 causes abnormal and persistent hyperactivation of Cdk2 and Cdc2 due to Tyr-15 dephosphorylation. These effects were associated with hyperphosphorylation of the upstream regulatory kinase Myt1 and Wee1. They were not observed with the anti-mitotic compounds. Furthermore, the S-phase inhibitors PD179483 and PD166326, but not the anti-mitotic compounds, inhibit Wee1 in vitro at concentrations that cause S-phase block in vivo. These data identify a novel subset of Pyridopyrimidine compounds which are inhibitors of src and Wee1 kinases and which inhibit tumor cell growth through cell cycle arrest in mid S-phase.
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a novel Pyridopyrimidine inhibitor of abl kinase is a picomolar inhibitor of bcr abl driven k562 cells and is effective against sti571 resistant bcr abl mutants
Clinical Cancer Research, 2003Co-Authors: David R Huron, Alan J Kraker, Mercedes E Gorre, Charles L Sawyers, Neal Rosen, Mark M MoasserAbstract:Inhibition of the constitutively active Bcr-abl tyrosine kinase(TK) by STI571 has proven to be a highly effective treatment for chronic myelogenous leukemia (CML). However, STI571 is only transiently effective in blast crisis, and drug resistance emerges by amplification of or development of mutational changes in Bcr-abl. We have screened a family of TK inhibitors of the pyrido [2,3- d ]pyrimidine class, unrelated to STI571, and describe here a compound with substantial activity against STI-resistant mutant Bcr-abl proteins. This compound, PD166326, is a dual specificity TK inhibitor and inhibits src and abl in vitro with IC 50 s of 6 and 8 nm respectively. PD166326 inhibits the growth of K562 cells with IC 50 of 300 pm, leading to apoptotic G 1 arrest, whereas non-Bcr-abl cell types require >1000 times higher concentrations. We tested the effects of PD166326 on two of the clinically observed STI571-resistant Bcr-abl mutants. PD166326 potently inhibits the E255K mutant Bcr-abl protein and the growth of Bcr-ablE255K-driven cells. The T315I mutant Bcr-abl protein, which is mutated within the ATP-binding pocket, is resistant to PD166326; however, the growth of Bcr-ablT315I-driven cells is partially sensitive to this compound, likely through the inhibition of Bcr-abl effector pathways. These findings show that TK drug resistance is a structure-specific phenomenon and can be overcome by TK inhibitors of other structural classes, suggesting new approaches for future anticancer drug development. PD166326 is a prototype of a new generation of anti-Bcr-abl compounds with picomolar potency and substantial activity against STI571-resistant mutants.
Oktay Arslan - One of the best experts on this subject based on the ideXlab platform.
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synthesis of carbazole bearing Pyridopyrimidine substituted sulfonamide derivatives and studies their carbonic anhydrase enzyme activity
Journal of Biochemical and Molecular Toxicology, 2019Co-Authors: Arleta Rifatinixha, Mustafa Arslan, Nahit Gencer, Kubra Cikrikici, Basak Gokce, Oktay ArslanAbstract:The synthesis of carbazole containing Pyridopyrimidine-substituted sulfonamide derivatives (3a-i) and their inhibitory effects on human carbonic anhydrase (hCA) I and II were studied. Spectral data and elemental analysis confirmed the structures of the compounds synthesized. The results show that all the synthesized compounds inhibited the CA I and II activities. Among them, 3a was found to be the most active ( K i : 14 µM) for hCA I and 3f ( K i : 126 µM) for hCA II.
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development of carbazole bearing Pyridopyrimidine substituted urea thiourea as polyphenol oxidase inhibitors synthesis biochemistry and theoretical studies
Archives of Physiology and Biochemistry, 2019Co-Authors: Arleta Rifati Nixha, Oktay Arslan, Nahit Gencer, Adem Ergun, Mustafa ArslanAbstract:Polyphenol oxidase (Tyrosinase, PPO) has received considerable attention, since it is the key enzyme in melanin biosynthesis. In this study, we investigated prepared novel carbazole-containing Pyridopyrimidine-substituted with urea and thiourea derivatives and their PPO activities on the diphenolase activity of banana tyrosinase. The structures of the compounds synthesized were confirmed by 1 H NMR, 13 C NMR, FTIR and elemental analysis. PPO enzyme was purified from banana on an affinity gel comprised of Sepharose 4B-L-tyrosine-p-amino benzoic acid. For evaluating the enzyme activity, the synthesised compounds were subjected to tyrosinase inhibition assay using catechol as substrate. While some of the compounds (6, 7, 8f, 8h, 8i, 8j) showed enzyme inhibitor effect, some of them (8a, 8b, 8c, 8d, 8e, 8g, 8k) activated the PPO enzyme activity. Gaussian software was used for the molecular calculations to explain the results for the prepared compounds.
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Development of carbazole-bearing Pyridopyrimidine-substituted urea/thiourea as polyphenol oxidase inhibitors: synthesis, biochemistry, and theoretical studies
'Informa UK Limited', 2019Co-Authors: Arleta Rifati Nixha, Nahit Gencer, Oktay Arslan, Adem Ergun, Arslan MustafaAbstract:Polyphenol oxidase (Tyrosinase, PPO) has received considerable attention, since it is the key enzyme in melanin biosynthesis. In this study, we investigated prepared novel carbazole-containing Pyridopyrimidine-substituted with urea and thiourea derivatives and their PPO activities on the diphenolase activity of banana tyrosinase. The structures of the compounds synthesized were confirmed by 1 H NMR, 13 C NMR, FTIR and elemental analysis. PPO enzyme was purified from banana on an affinity gel comprised of Sepharose 4B-L-tyrosine-p-amino benzoic acid. For evaluating the enzyme activity, the synthesised compounds were subjected to tyrosinase inhibition assay using catechol as substrate. While some of the compounds (6, 7, 8f, 8h, 8i, 8j) showed enzyme inhibitor effect, some of them (8a, 8b, 8c, 8d, 8e, 8g, 8k) activated the PPO enzyme activity. Gaussian software was used for the molecular calculations to explain the results for the prepared compounds
Terry L Bowlin - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationships of a novel pyranopyridine series of gram negative bacterial efflux pump inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Son T Nguyen, Steven M Kwasny, Xiaoyuan Ding, Steven C Cardinale, Courtney T Mccarthy, Hongsuk Kim, Hiroshi Nikaido, Norton P Peet, John D Williams, Terry L BowlinAbstract:Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the Pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.
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structure activity relationships of a novel pyranopyridine series of gram negative bacterial efflux pump inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Son T Nguyen, Steven M Kwasny, Xiaoyuan Ding, Steven C Cardinale, Courtney T Mccarthy, Hiroshi Nikaido, Norton P Peet, John D Williams, Terry L Bowlin, Timothy J OppermanAbstract:Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the Pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.
Son T Nguyen - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationships of a novel pyranopyridine series of gram negative bacterial efflux pump inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Son T Nguyen, Steven M Kwasny, Xiaoyuan Ding, Steven C Cardinale, Courtney T Mccarthy, Hongsuk Kim, Hiroshi Nikaido, Norton P Peet, John D Williams, Terry L BowlinAbstract:Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the Pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.
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structure activity relationships of a novel pyranopyridine series of gram negative bacterial efflux pump inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Son T Nguyen, Steven M Kwasny, Xiaoyuan Ding, Steven C Cardinale, Courtney T Mccarthy, Hiroshi Nikaido, Norton P Peet, John D Williams, Terry L Bowlin, Timothy J OppermanAbstract:Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the Pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.
Daniel Fourmy - One of the best experts on this subject based on the ideXlab platform.
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Exploring the binding pocket for Pyridopyrimidine ligands at the CCK1 receptor by molecular docking.
Journal of Molecular Modeling, 2008Co-Authors: Amel Toumi-maouche, Daniel Fourmy, Boubekeur Maouche, Safia Tairi-kellou, Salima El-aoufi, Mercedes Martin-martinez, Rosario Gonzalez-muniz, Bernard MaigretAbstract:Pyridopyrimidine-based analogues are among the most highly potent and selective antagonists of cholecystokinin receptor subtype-1 (CCK1R) described to date. To better understand the structural and chemical features responsible for the recognition mechanism, and to explore the binding pocket of these compounds, we performed automated molecular docking using GOLD2.2 software on some derivatives with structural diversity, and propose a putative binding conformation for each compound. The docking protocol was guided by the key role of the Asn333 residue, as revealed by site directed mutagenesis studies. The results suggest two putative binding modes located in the same pocket. Both are characterized by interaction with the main residues revealed by experiment, Asn333 and Arg336, and differ in the spatial position of the Boc-Trp moiety of these compounds. Hydrophobic contacts with residues Thr117, Phe107, Ile352 and Ile329 are also in agreement with experimental data. Despite the poor correlation obtained between the estimated binding energies and the experimental activity, the proposed models allow us to suggest a plausible explanation of the observed binding data in accordance with chemical characteristics of the compounds, and also to explain the observed diastereoselectivity of this family of antagonists towards CCK1R. The most reasonable selected binding conformations could be the starting point for future studies.
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combination of molecular modeling site directed mutagenesis and sar studies to delineate the binding site of Pyridopyrimidine antagonists on the human cck1 receptor
Journal of Medicinal Chemistry, 2005Co-Authors: Mercedes Martinmartinez, Anne Marty, Maud Jourdan, Chantal Escrieut, Elodie Archer, Rosario Gonzalezmuniz, Teresa M Garcialopez, Bernard Maigret, Rosario Herranz, Daniel FourmyAbstract:A rational combination of site-directed mutagenesis studies, structure-activity relationships, and dynamic-based docking of Pyridopyrimidine-derived CCK1R antagonists into a refined three-dimensional model of the CCK1R allowed us to identify the receptor residues and the ligand functional groups implicated in the molecular recognition process. Our results provided unambiguous evidence that the binding site of these antagonists is overlapping that of the C-terminal tetrapeptide of CCK. In particular, Asn333 and Arg336 residues of the CCK1R are essential for high-affinity binding of these ligands. Moreover, the 2-aryl group in the Pyridopyrimidine derivatives shares the same binding pocket as the C-terminal Phe side chain of CCK. Our [Pyridopyrimidine.CCK1R] complex model is consistent with previous suggestions concerning the molecular basis that governs functional activity and provides useful considerations about the high CCK1 versus CCK2 selectivity of our derivatives and could contribute to fine-tune the rational design of new molecules with optimized properties.
