Knoevenagel-IMHDA and -IMSDA sequences for the synthesis of chiral condensed O,N-, S,N- and N-heterocycles.

Domino Knoevenagel-cyclization reactions of styrene substrates, containing an -(-formyl)aryl subunit, were carried out with -substituted 2-cyanoacetamides to prepare tetrahydro-4-pyrano[3,4-]quinolone and hexahydrobenzo[]phenanthridine derivatives by competing IMHDA and IMSDA cyclization, respectively. The diastereoselective IMHDA step with α,β-unsaturated amide, thioamide, ester and ketone subunits as a heterodiene produced condensed chiral tetrahydropyran or thiopyran derivatives, which in the case of Meldrum's acid were reacted further with amine nucleophiles in a multistep domino sequence. In order to simplify the benzene-condensed tricyclic core of the targets and get access to hexahydro-1-pyrano[3,4-]pyridine derivatives, a truncated substrate was reacted with cyclic and acyclic active methylene reagents in diastereoselective Knoevenagel-IMHDA reactions to prepare novel condensed heterocyclic scaffolds.

Toward target 2035: EUbOPEN - a public-private partnership to enable & unlock biology in the open.

Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public-private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents.

Covalent Inhibitors of KEAP1 with Exquisite Selectivity.

The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders.

Correction: Agbadua et al. Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors. 2022, , 1832.

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Structure-Guided Discovery of Selective USP7 Inhibitors with In Vivo Activity.

Inhibition of ubiquitin-specific protease 7, USP7, has been proposed as a mechanism to affect many disease processes, primarily those implicated in oncology. The bound crystal structure of a published high-throughput screening hit with low-micromolar affinity for USP7 identified three regions of the compound for structure-guided optimization. Replacing one side of the compound with different aromatic moieties gave little improvement in affinity, and the central piperidine could not be improved.

High density information storage through isotope ratio encoding.

The need for reliable information storage is on a steep rise. Sequence-defined polymers, particularly oligonucleotides, are already in use in several areas, while compound mixtures also offer a simple way for storing information. We investigated the use of a set of isotopologues in information storage by mixing, where the information is stored in the form of a mass spectrometric (MS) fingerprint of the mixture.

Synthesis and Systematic Investigation of Lepidiline A and Its Gold(I), Silver(I), and Copper(I) Complexes Using In Vitro Cancer Models and Multipotent Stem Cells.

The imidazole alkaloid lepidiline A from the root of has a moderate to low in vitro anticancer effect. Our aim was to extend cytotoxicity investigations against a panel of cancer cells, including multidrug-resistant cancer cells, and multipotent stem cells. Lepidiline A is a N-heterocyclic carbene precursor, therefore a suitable ligand source for metal complexes.

Competing Domino Knoevenagel-Cyclization Sequences with -Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of -arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the -vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC values was identified for some of the novel scaffolds.

Merger of Visible Light-Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α-Alkylation of Aldehydes.

The electron donor-acceptor complex-enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α-alkylated aldehydes without an external photoredox catalyst. The photosensitizer-free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales.

Discovery and biocatalytic characterization of opine dehydrogenases by metagenome mining.

Enzymatic processes play an increasing role in synthetic organic chemistry which requires the access to a broad and diverse set of enzymes. Metagenome mining is a valuable and efficient way to discover novel enzymes with unique properties for biotechnological applications. Here, we report the discovery and biocatalytic characterization of six novel metagenomic opine dehydrogenases from a hot spring environment (mODHs) (EC 1.

Visible-Light-Induced Synthesis of Branched Ethers via Multicomponent Reactions.

The Spin-Center Shift (SCS) elimination is a specific way for the generation of radicals with relevance in synthetic and biochemical pathways. The combination of SCS-mediated radical chemistry and atom-transfer radical addition (ATRA) offers new directions in diversity-oriented chemical synthesis. Herein, we report a photoredox three-component reaction of α-acyloxy--heterocycles as radical precursors, styrene derivatives as radical trapping agents, and alcohols as nucleophilic quenchers.

Opine dehydrogenases, an underexplored enzyme family for the enzymatic synthesis of chiral amines.

Opines and opine-type chemicals are valuable natural products with diverse biochemical roles, and potential synthetic building blocks of bioactive compounds. Their synthesis involves reductive amination of ketoacids with amino acids. This transformation has high synthetic potential in producing enantiopure secondary amines.

Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice.

Background & Aims: Oxidative stress is recognized as a major driver of non-alcoholic steatohepatitis (NASH) progression. The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, as well as detoxification, and thus appear to be attractive targets for the treatment of NASH.

Methods: Molecular modeling and X-ray crystallography were used to design S217879 - a small molecule that could disrupt the KEAP1-NRF2 interaction.

Highly Oxidized Ecdysteroids from a Commercial Root Extract as Potent Blood-Brain Barrier Protective Agents.

Ecdysteroid-containing herbal extracts, commonly prepared from the roots of , are marketed worldwide as a "green" anabolic food supplement. Herein are reported the isolation and complete H and C NMR signal assignments of three new minor ecdysteroids (compounds -) from this extract. Compound was identified as a possible artifact that gradually forms through the autoxidation of calonysterone.

Utilizing the H-N NMR Methods for the Characterization of Isomeric Human Milk Oligosaccharides.

Human milk oligosaccharides (HMOs) are structurally complex unconjugated glycans that are the third largest solid fraction in human milk after lactose and lipids. HMOs are in the forefront of research since they have been proven to possess beneficial health effects, especially on breast-fed neonates. Although HMO research is a trending topic nowadays, readily available analytical methods suitable for the routine investigation of HMOs are still incomplete.

Isotope Ratio Encoding of Sequence-Defined Oligomers.

Information storage at the molecular level commonly entails encoding in the form of ordered sequences of different monomers and subsequent fragmentation and tandem mass spectrometry analysis to read this information. Recent approaches also include the use of mixtures of distinct molecules noncovalently bonded to one another. Here, we present an alternate isotope ratio encoding approach utilizing deuterium-labeled monomers to produce hundreds of oligomers endowed with unique isotope distribution patterns.

Enantioselective Cyclopropanation Catalyzed by Gold(I)-Carbene Complexes.

The formation of polysubstituted cyclopropane derivatives in the gold(I)-catalyzed reaction of olefins and propargylic esters is a potentially useful transformation to generate diversity, therefore any method in which its stereoselectivity could be controlled is of significant interest. We prepared and tested a series of chiral gold(I)-carbene complexes as a catalyst in this transformation. With a systematic optimization of the reaction conditions, we were able to achieve high enantioselectivity in the test reaction while the selectivity of the transformation was independent of the catalyst.

Oxidized Resveratrol Metabolites as Potent Antioxidants and Xanthine Oxidase Inhibitors.

Resveratrol is a well-known natural polyphenol with a plethora of pharmacological activities. As a potent antioxidant, resveratrol is highly oxidizable and readily reacts with reactive oxygen species (ROS). Such a reaction not only leads to a decrease in ROS levels in a biological environment but may also generate a wide range of metabolites with altered bioactivities.

CCP4 Cloud for structure determination and project management in macromolecular crystallography.

Nowadays, progress in the determination of three-dimensional macromolecular structures from diffraction images is achieved partly at the cost of increasing data volumes. This is due to the deployment of modern high-speed, high-resolution detectors, the increased complexity and variety of crystallographic software, the use of extensive databases and high-performance computing. This limits what can be accomplished with personal, offline, computing equipment in terms of both productivity and maintainability.

Targeting non-alcoholic fatty liver disease: Design, X-ray co-crystal structure and synthesis of 'first-in-kind' inhibitors of serine/threonine kinase25.

We describe the synthesis of a series of 3-t-butyl 5-aminopyrazole p-substituted arylamides as inhibitors of serine-threonine25 (STK25), an enzyme implicated in the progression of non-alcoholic fatty liver disease (NAFLD). Appending a p-N-pyrrolidinosulphonamide group to the arylamide group led to a 'first-in kind' inhibitor with IC = 228 nM. A co-crystal structure with STK 25 revealed productive interactions which were also reproduced using molecular docking.

Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics.

On the basis of the knowledge that the proline-rich hot spot RPP region of P(151)PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22 (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47 (p47), we designed a mimetic of the tripeptide based on NMR and X-ray crystallographic data for the p22(151-161) peptide PPSNRPPA with a peptide construct. Incorporation of the synthetic pseudo-triproline mimetic Pro-Pro-Cyp in a molecule derived from molecular modeling studies led to only a 7-fold diminution in activity in a surface plasmon resonance assay relative to the same molecule containing the natural Pro-Pro-Pro tripeptide. The alternative sequence corresponding to a Pro-Cyp-Pro insertion was inactive.

Building Biological Relevance Into Integrative Modelling of Macromolecular Assemblies.

Recent advances in structural biophysics and integrative modelling methods now allow us to decipher the structures of large macromolecular assemblies. Understanding the dynamics and mechanisms involved in their biological function requires rigorous integration of all available data. We have developed a complete modelling pipeline that includes analyses to extract biologically significant information by consistently combining automated and interactive human-guided steps.

In vivo Evidence of Arterial Dynamic Properties Alteration in Atherosclerotic Rabbit.

Objectives: Atherosclerosis severely damages the arterial wall. The aim of this study was to assess in vivo, for the first time, arterial dynamic properties, reactivity, and stiffness in atherosclerotic (ATH) rabbits.

Methods: The rabbits were fed with 0.