The Experts below are selected from a list of 546801 Experts worldwide ranked by ideXlab platform
Brian Juba - One of the best experts on this subject based on the ideXlab platform.
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Aminopyrazole Carboxamide Bruton’s Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning
ACS medicinal chemistry letters, 2018Co-Authors: Mark E. Schnute, Stephen E. Benoit, Ingrid P. Buchler, Nicole Caspers, Margaret L. Grapperhaus, Seungil Han, Rajeev Hotchandani, Nelson Huang, Robert Hughes, Brian JubaAbstract:Potent Covalent inhibitors of Bruton’s tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based Covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-Covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide Covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.
Fabien Silly - One of the best experts on this subject based on the ideXlab platform.
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Temperature-Triggered Sequential On-Surface Synthesis of One and Two Covalently Bonded Porous Organic Nanoarchitectures on Au(111)
Journal of Physical Chemistry C, 2017Co-Authors: David Peyrot, Mathieu Silly, Fabien SillyAbstract:Subtle variations of surface temperature can drastically influence the on-surface synthesis of two-dimensional Covalent graphene nanoarchitectures. The structure of the engineered nanoarchitectures not only results from the temperature-activation of the catalytic process, but it is also governed by the temperature-dependent geometry of intermolecular assembly. The sequential engineering of porous organic nanoarchitectures based on the Covalent Ullmann coupling of star-shaped 1,3,5-tris(3,5-dibromophenyl)benzene molecules on Au(111) in vacuum is investigated using scanning tunneling microscopy and X-ray photoemission spectroscopy. This molecule can form one-Covalent-bond or two-Covalent-bonds with neighboring molecules. At room temperature, the molecules self-assemble into a porous halogen-bonded network stabilized by two types of X 3 synthons. One-Covalent-bond dimers appear on the surface after annealing at 145 °C. One-Covalent-bond chains are created after annealing at 170 °C. Most of the molecules are bonded to two neighbors. One-Covalent-bond hexagons as well as two-Covalent-bond dimers are appearing on the surface after annealing at 175 °C. Annealing at 275 °C leads to the formation of a porous 2D hexagonal two-Covalent-bond nanoarchitecture. STM images show that the number of intermolecular Covalent bonds as well as the number of Covalently bonded molecular neighbors increases as the temperature rises. Core level spectroscopy shows that the molecules are fully dehalogenated after annealing at 260 °C. These observations show that dibromophenyl-based molecules are promising organic compounds to hierarchically and selectively engineer Covalent porous graphene nanoarchitectures having different structures.
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On-Surface Synthesis of Two-Dimensional Covalent Organic Structures versus Halogen-Bonded Self-Assembly: Competing Formation of Organic Nanoarchitectures
ACS Nano, 2016Co-Authors: David Peyrot, Fabien SillyAbstract:The competition between the on-surface synthesis of Covalent nanoarchitectures and the self-assembly of star-shaped 1,3,5-Tris(4-iodophenyl)benzene molecules on Au(111) in vacuum is investigated using scanning tunneling microscopy above room temperature. The molecules form Covalent polygonal nanoachitectures at the gold surface step edges and at the elbows of the gold reconstruction at low coverage. With coverage increasing two-dimensional halogen-bonded structures appear and grow on the surface terraces. Two different halogen-bonded nanoarchitectures are coexisting on the surface and hybrid Covalent-halogen bonded structures are locally observed. At high coverage Covalent nanoarchitectures are squeezed at the domain boundary of the halogen-bonded structures. The competitive growth between the Covalent and halogen-bonded nanoarchitectures leads to formation of a two-layer film above one monolayer deposition. For this coverage, the Covalent nanoarchitectures are propelled on top of the halogen-bonded first layer. These observations open up new opportunities for decoupling Covalent nanoarchitectures from catalytically active and metal surfaces in vacuum.
Alexander V. Statsyuk - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Covalent enzyme inhibitors using virtual docking of Covalent fragments
Bioorganic & medicinal chemistry letters, 2018Co-Authors: Sandipan Roy Chowdhury, Stefan G. Kathman, Steven Kennedy, Kai Zhu, Rama K. Mishra, Patrick Chuong, Alyssa Uyen Nguyen, Alexander V. StatsyukAbstract:Here we present a virtual docking screen of 1648 commercially available Covalent fragments, and identified Covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of Covalent fragments as an approach to discover Covalent enzyme inhibitors.
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Covalent Tethering of Fragments For Covalent Probe Discovery.
MedChemComm, 2016Co-Authors: Stefan G. Kathman, Alexander V. StatsyukAbstract:Covalent probes and drugs have found widespread use as research tools and clinical agents. Covalent probes are useful because of their increased intracellular potency and because Covalent labeling of cellular proteins can be tracked using click chemistry. Covalent drugs, on the other hand, can overcome drug resistance toward their reversible counterparts. The discovery of Covalent probes and drugs usually follows two trajectories: Covalent natural products and their analogues are used directly as Covalent probes or drugs; or alternatively, a non-Covalent probe is equipped with a reactive group and converted into a Covalent probe. In both cases, there is a need to either have a natural product or a potent non-Covalent scaffold. The alternative approach to discover Covalent probes is to start with a drug-like fragment that already has an electrophile, and then grow the fragment into a potent lead compound. In this approach, the electrophilic fragment will react Covalently with the target protein, and therefore the initial weak binding of the fragment can be amplified over time and detected using mass spectrometry. With this approach the surface of the protein can be interrogated with a library of Covalent fragments to identify Covalent drug binding sites. One challenge with this approach is the danger of non-specific Covalent labeling of proteins with Covalent fragments. The second challenge is the risk of selecting the most reactive fragment rather than the best binder if the Covalent fragments are screened in mixtures. This review will highlight how Covalent tethering was developed, its current state, and its future.
Mark E. Schnute - One of the best experts on this subject based on the ideXlab platform.
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Aminopyrazole Carboxamide Bruton’s Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning
ACS medicinal chemistry letters, 2018Co-Authors: Mark E. Schnute, Stephen E. Benoit, Ingrid P. Buchler, Nicole Caspers, Margaret L. Grapperhaus, Seungil Han, Rajeev Hotchandani, Nelson Huang, Robert Hughes, Brian JubaAbstract:Potent Covalent inhibitors of Bruton’s tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based Covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-Covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide Covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.
David Peyrot - One of the best experts on this subject based on the ideXlab platform.
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Temperature-Triggered Sequential On-Surface Synthesis of One and Two Covalently Bonded Porous Organic Nanoarchitectures on Au(111)
Journal of Physical Chemistry C, 2017Co-Authors: David Peyrot, Mathieu Silly, Fabien SillyAbstract:Subtle variations of surface temperature can drastically influence the on-surface synthesis of two-dimensional Covalent graphene nanoarchitectures. The structure of the engineered nanoarchitectures not only results from the temperature-activation of the catalytic process, but it is also governed by the temperature-dependent geometry of intermolecular assembly. The sequential engineering of porous organic nanoarchitectures based on the Covalent Ullmann coupling of star-shaped 1,3,5-tris(3,5-dibromophenyl)benzene molecules on Au(111) in vacuum is investigated using scanning tunneling microscopy and X-ray photoemission spectroscopy. This molecule can form one-Covalent-bond or two-Covalent-bonds with neighboring molecules. At room temperature, the molecules self-assemble into a porous halogen-bonded network stabilized by two types of X 3 synthons. One-Covalent-bond dimers appear on the surface after annealing at 145 °C. One-Covalent-bond chains are created after annealing at 170 °C. Most of the molecules are bonded to two neighbors. One-Covalent-bond hexagons as well as two-Covalent-bond dimers are appearing on the surface after annealing at 175 °C. Annealing at 275 °C leads to the formation of a porous 2D hexagonal two-Covalent-bond nanoarchitecture. STM images show that the number of intermolecular Covalent bonds as well as the number of Covalently bonded molecular neighbors increases as the temperature rises. Core level spectroscopy shows that the molecules are fully dehalogenated after annealing at 260 °C. These observations show that dibromophenyl-based molecules are promising organic compounds to hierarchically and selectively engineer Covalent porous graphene nanoarchitectures having different structures.
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On-Surface Synthesis of Two-Dimensional Covalent Organic Structures versus Halogen-Bonded Self-Assembly: Competing Formation of Organic Nanoarchitectures
ACS Nano, 2016Co-Authors: David Peyrot, Fabien SillyAbstract:The competition between the on-surface synthesis of Covalent nanoarchitectures and the self-assembly of star-shaped 1,3,5-Tris(4-iodophenyl)benzene molecules on Au(111) in vacuum is investigated using scanning tunneling microscopy above room temperature. The molecules form Covalent polygonal nanoachitectures at the gold surface step edges and at the elbows of the gold reconstruction at low coverage. With coverage increasing two-dimensional halogen-bonded structures appear and grow on the surface terraces. Two different halogen-bonded nanoarchitectures are coexisting on the surface and hybrid Covalent-halogen bonded structures are locally observed. At high coverage Covalent nanoarchitectures are squeezed at the domain boundary of the halogen-bonded structures. The competitive growth between the Covalent and halogen-bonded nanoarchitectures leads to formation of a two-layer film above one monolayer deposition. For this coverage, the Covalent nanoarchitectures are propelled on top of the halogen-bonded first layer. These observations open up new opportunities for decoupling Covalent nanoarchitectures from catalytically active and metal surfaces in vacuum.
