Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Applications of Diglycolamide Based Solvent Extraction Processes in Spent Nuclear Fuel Reprocessing,Part 1: TODGA

Over the last decade there has been much interest in the applications of diglycolamide (DGA) ligands for the extraction of the trivalent lanthanide and actinide ions from PUREX high active raffinates or dissolved spent nuclear fuel. Of the DGAs, the N,N,N’,N’-tetraoctyldiglycolamide (TODGA) is the best known and most widely studied. A number of new actinide separation processes have been proposed based on extraction with TODGA. This review covers TODGA-based processes and extraction data, specifically focusing on how phase modifiers have been used to increase metal loading and thus enhance the operating process envelopes. Effects of third phase formation and the organic phase speciation are reviewed in this context. Relevant aspects of the extraction chemistry of important solvents (TODGA-modifier-diluent combinations) are described and their performances demonstrated by a consideration of the published flowsheet tests. It is seen that modifiers are successfully enabling the use of TODGA in actinide separation processes but to date the identification and testing of suitable modifiers has been rather empirical. There is a growing understanding of the fundamental chemistry occurring in the organic phase and how that affects extractant speciation and metal loading capacity but studies are still needed if TODGA-based flowsheets are to become an industrially deployable option for minor actinide (MA) recovery processes.     

Aqueous One-pot Synthesis of Glycopolymers by Glycosidase-catalyzed Glycomonomer Synthesis Using 4,6-Dimetoxy Triazinyl Glycoside Followed by Radical Polymerization

Glycopolymers have attracted increased attention as functional polymeric materials, and simple methods for synthesizing glycopolymers remain needed. This paper reports the aqueous one-pot and chemoenzymatic synthesis of four types of glycopolymers via two reactions: the β-galactosidase-catalyzed glycomonomer synthesis using 4,6-dimetoxy triazinyl β-D-galactopyranoside and hydroxy group-containing (meth)acrylamide and (meth)acrylate derivatives as the activated glycosyl donor substrate and as the glycomonomer precursors, respectively, followed by radical copolymerization of the resulting glycomonomer and excess glycomonomer precursor without isolating the glycomonomers. The resulting glycopolymers bearing galactose moieties exhibited specific and strong interactions with the lectin peanut agglutinin as glycoclusters.     

Computer Vision and Pattern Recognition 2020

International Journal of Computer Vision -     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

Mobile Lösungen für den Vertrieb bei Finanzdienstleistern

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