The nature of the excited state renders the development of chiral catalysts for enantioselective photochemical reactions a considerable challenge. The absorption of a 400 nm photon corresponds to an energy uptake of approximately 300 kJ mol(-1) . Given the large distance to the ground state, innovative concepts are required to open reaction pathways that selectively lead to a single enantiomer of the desired product. This Review outlines the two major concepts of homogenously catalyzed enantioselective processes. The first part deals with chiral photocatalysts, which intervene in the photochemical key step and induce an asymmetric induction in this step. In the second part, reactions are presented in which the photochemical excitation is mediated by an achiral photocatalyst and the transfer of chirality is ensured by a second chiral catalyst (dual catalysis).
Celastrol is a natural pentacyclic
triterpene used in traditional
Chinese medicine with significant weight-lowering effects. Celastrol-administered
mice at 100 μg/kg decrease food consumption and body weight
via a leptin-dependent mechanism, yet its molecular targets in this
pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced
weight loss is largely mediated by the inhibition of leptin negative
regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell
PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show
in vitro that celastrol binds reversibly and inhibits noncompetitively
PTP1B and TCPTP. NMR data map the binding site to an allosteric site
in the catalytic domain that is in proximity of the active site. By
using a panel of PTPs implicated in hypothalamic leptin signaling,
we show that celastrol additionally inhibited PTEN and SHP2 but had
no activity toward other phosphatases of the PTP family. These results
suggest that PTP1B and TCPTP in the ARC are essential for celastrol’s
weight lowering effects in adult obese mice.
The title compounds underwent a facile and high-yielding addition reaction (19 examples, 66-99% yield) with various N-(trimethylsilyl)methyl-substituted amines upon irradiation with visible light and catalysis by a metal complex. If the alkylidene substituent is non-symmetric and if the reaction is performed in the presence of a chiral hydrogen-bonding template, products are obtained with significant enantioselectivity (58-72% ee) as a mixture of diastereoisomers. Mechanistic studies suggest a closed catalytic cycle for the photoactive metal complex. However, the silyl transfer from the amine occurs not only to the product, but also to the substrate, and interferes with the desired chirality transfer.
Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14−PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14−PEX5 protein−protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14−PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.
Two years since the outbreak of the novel coronavirus SARS-CoV-2 pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side-effect. One alternative, with structural similarities to heparin is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights, inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using NMR spectroscopy and LC-MS, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective at inhibiting cell infection than low molecular weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.
Die Natur des angeregten Zustands macht die Entwicklung chiraler Katalysatoren für enantioselektive photochemische Reaktionen zu einer enormen Herausforderung. Die Absorption eines 400‐nm‐Photons entspricht einer Energieaufnahme von etwa 300 kJ mol−1. Es bedarf innovativer Konzepte, um in einem derart großen Abstand vom Grundzustand Reaktionspfade zu eröffnen, die gezielt zu einem Enantiomer einer chiralen Verbindung führen. Hier werden die beiden wesentlichen Vorgehensweisen für homogen katalysierte, enantioselektive Prozesse diskutiert. Im ersten Teil werden chirale Photokatalysatoren besprochen, die in den photochemischen Schlüsselschritt eingreifen und in diesem Schritt eine asymmetrische Induktion bewirken. Im zweiten Teil werden Reaktionen vorgestellt, in denen die photochemische Anregung durch einen achiralen Katalysator erfolgt und die asymmetrische Induktion durch einen zweiten chiralen Katalysator gewährleistet wird (duale Katalyse).
This paper presents a generic scheme to extract traffic information from both optical satellite imagery and optical airborne image sequences. The extraction is based on an explicit semantic model of traffic, from which, depending on the characteristics of the input data, different strategies for vehicle detection, vehicle queue extraction and motion estimation are derived. The model comprises different scales to exploit the scale‐dependent properties of traffic imaged by optical sensors. It is furthermore extended by context information to include knowledge about background objects as well as metadata from a road database in a consistent way. Various tests with different input data have been carried out and compared with manually acquired ground truth data of vehicles and vehicle tracks. The results show clearly the high potential of airborne and spaceborne traffic monitoring, but also indicate room for methodological improvements and exhibit some inherent sensor‐related drawbacks.
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