The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux ...and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signalling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metabolism. New strategies for the pharmacological manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Conspectus The field of supramolecular chemistry has its foundation in molecular recognition and selective binding of guest molecules, often with remarkably strong binding affinities. The field ...evolved to leverage these favorable interactions between the host and its guest to catalyze simple, often biomimetic transformations. Drawing inspiration from these early studies, self-assembled supramolecular hosts continue to capture a significant amount of interest toward their development as catalysts for increasingly complex transformations. Nature often relies on microenvironments, derived from complex tertiary structures and a well-defined active site, to promote reactions with remarkable rate acceleration, substrate specificity, and product selectivity. Similarly, supramolecular chemists have become increasingly intrigued by the prospect that self-assembly of molecular components might generate defined and spatially segregated microenvironments that can catalyze complex transformations. Among the growing palette of supramolecular catalysts, an anionic, water-soluble, tetrahedral metal–ligand coordination host has found a range of applications in catalysis and beyond. Early work focused on characterizing and understanding this host and its various host–guest phenomena, which paved the path for exploiting these features to selectively promote desirable chemistries, including cyclizations, rearrangements, and bimolecular reactions. Although this early work matured into achievements of catalysis with dramatic rate accelerations as well as enantioenrichment, the afforded products were typically identical to those produced by background reactions that occurred outside of the host microenvironment. This Account describes our recent developments in the application of these anionic tetrahedral hosts as catalysts for organic and organometallic transformation. Inspiration from natural systems and unmet synthetic challenges led to supramolecular catalysis displaying unique divergences in reactivity to give products that are inaccessible from bulk solution. Additionally, these tetrahedral assemblies have been shown to catalyze a diverse range of transformations with notable rate acceleration over the uncatalyzed background reaction. The pursuit of complexity beyond supramolecular catalysis has since led to the integration of these tetrahedral catalysts in tandem with natural enzymes, as well as their application to dual catalysis to realize challenging synthetic reactions. Variation in the structure, including size and charge, of these tetrahedral catalysts has enabled recent studies that provide insights into connections between specific structural features of these hosts and their reactivities. These mechanistic studies reveal that the solvent exclusion properties, hydrophobic effects, confinement effects and electrostatic effects play important roles in the observed catalysis. Moreover, these features may be leveraged for the design of supramolecular catalysis beyond those described in this Account. Finally, the supramolecular chemistry detailed in this Account has presented the opportunity to emulate some of the mechanisms nature engages to achieve catalysis; however, this relationship need not be entirely unidirectional, as the examples describe herein can stand as simplified model systems for unravelling more complex biological processes.
Cellular cholesterol levels reflect a balance between uptake, efflux, and endogenous synthesis. Here we show that the sterol-responsive nuclear liver X receptor (LXR) helps maintain cholesterol ...homeostasis, not only through promotion of cholesterol efflux but also through suppression of low-density lipoprotein (LDL) uptake. LXR inhibits the LDL receptor (LDLR) pathway through transcriptional induction of Idol (inducible degrader of the LDLR), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduces, whereas LXR knockout increases, LDLR protein levels in vivo in a tissue-selective manner. Idol knockdown in hepatocytes increases LDLR protein levels and promotes LDL uptake. Conversely, adenovirus-mediated expression of Idol in mouse liver promotes LDLR degradation and elevates plasma LDL levels. The LXR-Idol-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake.
Biological systems are integrated networks constantly responding to internal and external stimulators. Understanding the intrinsic response to an imbalanced system provides the opportunity to develop ...therapeutic approaches to reinstate the natural balanced state. Increasing evidence suggests that members of the nuclear receptor superfamily integrate both inflammatory and metabolic signals to maintain homeostasis in immune cells such as macrophages and lymphocytes. PPAR and LXR are nuclear receptors activated by fatty acid and cholesterol derivatives respectively that control the expression of an array of genes involved in lipid metabolism and inflammation. Recent studies have uncovered distinct mechanisms for transcriptional regulation of metabolic and inflammatory target genes by PPAR and LXR and have expanded the biology of these receptors to include roles in alternative macrophage activation and adaptive immunity.
We have demonstrated that the microenvironment of a highly anionic supramolecular catalyst can mimic the active sites of enzymes and impart rate accelerations of a million-fold or more. However, ...these microenvironments can be challenging to study, especially in the context of understanding which specific features of the catalyst are responsible for its high performance. We report here the development of an experimental mechanistic probe consisting of two isostructural catalysts. When examined in parallel transformations, the behavior of these catalysts provides insight relevant to the importance of anionic host charge on reactivity. These two catalysts exhibit similar host-substrate interactions, but feature a significant difference in overall anionic charge (12– and 8–). Within these systems, we compare the effect of constrictive binding in a net neutral aza-Cope rearrangement. We then demonstrate how the magnitude of anionic host charge has an exceptional influence on the reaction rates for a Nazarov cyclization, evidenced by an impressive 680-fold change in reaction rate as a consequence of a 33% reduction in catalyst charge.
Computed descriptors for acyclic diaminocarbene ligands are developed in the context of a gold catalyzed enantioselective tandem 3,3-sigmatropic rearrangement-2+2-cyclization. Surrogate structures ...enable the rapid identification of parameters that reveal mechanistic characteristics. The observed selectivity trends are validated in a robust multivariate analysis facilitating the development of a highly enantioselective process.
This study offers a detailed mechanistic investigation of host–guest encapsulation behavior in a new enzyme–mimetic metal–ligand host and provides the first observation of a conformational selection ...mechanism (as opposed to induced fit) in a supramolecular system. The Ga4L4 host described features a C 3-symmetric ligand motif with meta-substituted phenyl spacers, which enables the host to initially self-assemble into an S 4-symmetric structure and then subsequently isomerize to a T-symmetric tetrahedron for better accommodation of a sufficiently large guest. Selective inversion recovery 1H NMR studies provide structural insights into the self-exchange behaviors of the host and the guest individually in this dynamic system. Kinetic analysis of the encapsulation–isomerization event revealed that increasing the concentration of guest inhibits the rate of host–guest relaxation, a key distinguishing feature of conformational selection. A comprehensive study of this simple enzyme mimic provides insight into analogous behavior in biophysics and enzymology and aims to inform the design of efficient self-assembled microenvironment catalysts.
Aryl and heteroaryl fluorides are growing to be dominant motifs in pharmaceuticals and agrochemicals, yet they are rare in both nature and commodity chemicals. As a consequence, there is an ...increasingly urgent need to develop mild, cost-effective, and scalable methods for fluorination. The most straightforward route to synthesize aryl fluorides is through the halide exchange “halex” reaction, but conditions, cost, and atom economy preclude most available methods from large-scale manufacturing processes. We report a new approach that leverages the cooperative action of 18-crown-6 ether and tetramethylammonium chloride to catalytically access the reactivity of tetramethylammonium fluoride and achieve halex fluorinations under mild conditions with operational ease. The described methodology readily converts both heteroaryl chlorides and aryl triflates to their corresponding (hetero)aryl fluorides in high yields and purities.
The scope and mechanism of the microenvironment-catalyzed C(sp3)−C(sp3) reductive elimination from transition metal complexes Au(III), Pt(IV) is explored. Experiments detailing the effect of ...structural perturbation of neutral and anionic spectator ligands, reactive alkyl ligands, solvent, and catalyst structure are disclosed. Indirect evidence for a coordinatively unsaturated encapsulated cationic intermediate is garnered via observation of several inactive donor-arrested inclusion complexes, including a crystallographically characterized encapsulated Au(III) cation. Finally, based on stoichiometric experiments under catalytically relevant conditions, a detailed mechanism is outlined for the dual supramolecular and platinum-catalyzed C–C coupling between methyl iodide and tetramethyltin. Determination of major platinum species present under catalytic conditions and subsequent investigation of their chemistry reveals an unexpected interplay between cis–trans isomerism and the supramolecular catalyst in a Pt(II)/Pt(IV) cycle, as well as several off-cycle reactions.
A simplified approach to quantum yield ( ϕ ) measurement using in situ LED NMR spectroscopy has been developed. The utility and performance of NMR actinometry has been demonstrated for the well-known ...chemical actinometers potassium ferrioxalate and o-nitrobenzaldehyde. A novel NMR-friendly actinometer, 2,4-dinitrobenzaldehyde, has been introduced for both 365 and 440 nm wavelengths. The method has been utilized successfully to measure the quantum yield of several recently published photochemical reactions.
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