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Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Total synthesis of phorboxazole a via de novo oxazole formation: Convergent total synthesis

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3-C17 and C18-C30 building blocks via formation of the C16-C18 oxazole, followed by macrolide ring closure involving an intramolecular Still-Genarri olefination at C2-C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product’s (2Z)-acrylate with remarkable geometrical selectivity. The C31-C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product’s oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation-cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3-C17 and C18-C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Synthesis of gold nanoparticle catalysts based on a new water-soluble ionic polymer

A new water-soluble methyl-imidazolium-based ionic polymer was synthesized by ring-opening metathesis polymerization that was subsequently used to prepare aqueous gold nanoparticle solutions which were characterized by UV-vis spectroscopy and transmission electron microscopy (TEM). The aqueous gold nanoparticle solutions were employed as catalysts in the reduction of p-nitrophenol and in the hydrogenation of cinnamaldehyde and were found to exhibit excellent activity under mild conditions.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Studies on ring-closing metathesis for the formation of the 11-membered ring system of daphnezomine C

For the purpose of synthesizing daphnezomine C, model systems were examined to see if the ring-closing metathesis (RCM) reaction could be applied to prepare an 11-membered ring system bearing a tri-substituted alkene. As a result, it was found that the connectivity pattern of the tethers bearing the reacting alkene moieties was crucial. Thus, whereas a system involving a single 1,3- or 1,4-disubstituted cyclohexane derivative did not give RCM products, a flexible system without any rings between the two terminal alkenes gave the cyclic product with a yield of up to 65% using the second generation Grubbs catalyst.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Electric Literature of 246047-72-3, Chemistry can be defined as the study of matter and the changes it undergoes. You¡¯ll sometimes hear it called the central science because it is the connection between physics and all the other sciences, starting with biology.246047-72-3, Name is (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium, molecular formula is C46H65Cl2N2PRu. In a patent, introducing its new discovery.

Divergent reactivity of alk-5-ynylidenecyclopropanes in the presence of the 1st or the 2nd generation Grubbs’ catalysts

Alk-5-ynylidenecyclopropanes, by virtue of being equipped with a strained cyclopropane system, can be divergently elaborated into bicyclo[3.3.0]octenes or exocyclopropylidenecycloalkenes depending on whether they react with the first or the second generation Grubbs’ ruthenium carbenes. While the highly reactive second generation system catalyses the formation of ring-closing metathesis products, the less [metathesis] active first generation carbene promotes an intramolecular [3 + 2] cycloaddition to give the bicarbocyclic skeletons.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Stereoselective synthesis of tetrahydrofuran spiro-beta-lactams by Ru-catalyzed metathesis of 7-oxabicyclo[2.2.1]heptenes

A new method for the synthesis of spiro-beta-lactams tethered to tetrahydrofuran rings is described. The procedure is based on Ru-catalyzed metathesis sequences with oxanorbornene precursors easily obtained by the Staudinger [2 + 2] cycloaddition of related imines.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Total synthesis and antibacterial properties of carbaplatensimycin

The chemical synthesis and biological evaluation of carbaplatensimycin, the carbon analogue of the recently reported antibiotic platensimycin has been accomplished. Carbaplatensimycin exhibited similar potency to the natural product as an antibacterial agent against a variety of strains, including methicilin- and vancomycin-resistant bacteria. Copyright

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Reference of 246047-72-3, Chemistry can be defined as the study of matter and the changes it undergoes. You¡¯ll sometimes hear it called the central science because it is the connection between physics and all the other sciences, starting with biology.246047-72-3, Name is (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium, molecular formula is C46H65Cl2N2PRu. In a patent, introducing its new discovery.

Sequence-Controlled Polymers Through Entropy-Driven Ring-Opening Metathesis Polymerization: Theory, Molecular Weight Control, and Monomer Design

The bulk properties of a copolymer are directly affected by monomer sequence, yet efficient, scalable, and controllable syntheses of sequenced copolymers remain a defining challenge in polymer science. We have previously demonstrated, using polymers prepared by a step-growth synthesis, that hydrolytic degradation of poly(lactic-co-glycolic acid)s is dramatically affected by sequence. While much was learned, the step-growth mechanism gave no molecular weight control, unpredictable yields, and meager scalability. Herein, we describe the synthesis of closely related sequenced polyesters prepared by entropy-driven ring-opening metathesis polymerization (ED-ROMP) of strainless macromonomers with imbedded monomer sequences of lactic, glycolic, 6-hydroxy hexanoic, and syringic acids. The incorporation of ethylene glycol and metathesis linkers facilitated synthesis and provided the olefin functionality needed for ED-ROMP. Ring-closing to prepare the cyclic macromonomers was demonstrated using both ring-closing metathesis and macrolactonization reactions. Polymerization produced macromolecules with controlled molecular weights on a multigram scale. To further enhance molecular weight control, the macromonomers were prepared with cis-olefins in the metathesis-active segment. Under these selectivity-enhanced (SEED-ROMP) conditions, first-order kinetics and narrow dispersities were observed and the effect of catalyst initiation rate on the polymerization was investigated. Enhanced living character was further demonstrated through the preparation of block copolymers. Computational analysis suggested that the enhanced polymerization kinetics were due to the cis-macrocyclic olefin being less flexible and having a larger population of metathesis-reactive conformers. Although used for polyesters in this investigation, SEED-ROMP represents a general method for incorporation of sequenced segments into molecular weight-controlled polymers.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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SYNTHESIS AND CHARACTERIZATION OF METATHESIS CATALYSTS

This invention relates generally to olefin metathesis catalysts, to the preparation of such compounds, compositions comprising such compounds, methods of using such compounds, and the use of such compounds in the metathesis of olefins and in the synthesis of related olefin metathesis catalysts. The invention has utility in the fields of catalysis, organic synthesis, polymer chemistry, and in industrial applications such as oil and gas, fine chemicals, and pharmaceuticals.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI

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Grubbs catalysts in intramolecular carbene C(sp3)-H insertion reactions from alpha-diazoesters

Grubbs catalysts are described as a useful alternative to promote intramolecular carbene C-H insertion from alpha-diazoesters. Moreover, no competition arises from the possible metathesis reactions on substrates bearing alkene and alkyne moieties. DFT calculations were also carried out to gain insight into the reaction mechanism involved in these transformations.

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Reference£º
Highly efficient and robust molecular ruthenium catalysts for water oxidation,
Catalysts | Special Issue : Ruthenium Catalysts – MDPI