Latest ArticlesUBE2C (Ubiquitin conjugating enzyme E2 C), a key regulator of cell cycle progression, is a promising target for discovery of antitumor agents. However, it is challenging to develop inhibitors of UBE2C owing to its lack of “druggable” pockets. BioPROTACs (biological proteolysis targeting chimeras) are a kind of protein-based degraders by fusing an adaptor to a subunit of E3 ligase for ubiquitination and subsequent proteasome-dependent degradation of target protein. We report herein the design and biological evaluation of a UBE2C-targeting bioPROTAC based on the NEL (novel E3 ligase) domain of bacterial E3 ligase IpaH9.8 and the UBE2C-binding WHB (winged-helix B) domain of APC2 (anaphase promoting complex subunit 2). The in vitro ubiquitination test and Mass Spectrometry analysis showed that the bioPROTAC could transfer ubiquitin to surface exposed lysines on UBE2C and catalyzed the formation of polyubiquitin chains. In addition, the transient co-expression experiment showed that the bioPROTAC could promote proteasomal degradation of heterologous UBE2C and rescue its downstream substrates in mammalian cells.
Immune rejection, poor biocompatibility and cytotoxicity have seriously stalled the widespread application of biometallic materials. To overcome these problems, biometallic materials with fast and sufficient osseointegration, antibacterial properties and long-term stability have attracted the attention of researchers worldwide. Surface modification is currently used as a general strategy to develop material coatings that will overcome these challenging requirements and achieve the successful performance of implants. In this study, we proposed a substrate surface-modification strategy based on biofilm CsgA proteins that promote rapid cell attachment, proliferation, and stabilization of the cytoskeleton. CsgA-based nano-coating is easy to fabricate and has superior performance, which is expected to expand the application of medical implants.
Organic electrosynthesis as an emerging green and advantageous alternative to traditional synthetic methods has achieved remarkable progress in recent years because sustainable electricity can be employed as traceless redox agents. To surmount the over-oxidation/reduction issues of direct electrolysis, mediated or indirect electrochemical processes are attaining remarkable significance and promoting the selectivity of products. Molecular electrocatalysts, benefiting from the easily electronic and steric modulation, suffers from readily degradation issue in most cases. Remarkably, heterogeneous catalysts have drawn more attention due to their high activity, stability, and recyclability. Hence, in this review, the most recent growth of heterogeneous catalysts modified electrodes for organic electrosynthesis were summarized, highlighting structural optimization and electrochemical performance of these materials as well as reaction mechanism. Furthermore, key challenges and future directions in this area were also discussed.
Chalcogenative sulfones (thiosulfonates and selenosulfonates), as reactants for organic transformations, are widely used and interesting because of their potential to react with nucleophiles, electrophiles, and free radicals. As stable radical reagents, the synthesis and applications of chalcogenative sulfones have opened up a novel pathway to synthesize many kinds of compounds containing sulfur or selenium motifs. However, despite the numerous recent works on the synthesis and applications of thiosulfonates and selenosulfonates as radical reagents, no review has yet provided a summary of the literature. In this paper, we aim to review the synthesis and applications strategies of chalcogenative sulfones as radical reagents reported over the past several decades. Different types of catalysis are discussed in this review: (ⅰ) metal catalysis; (ⅱ) visible-light catalysis; (ⅲ) synergistic catalysis; and (ⅲⅰ) other types. Concurrently, in visible-light catalysis and metallaphotoredox catalysis sections, we highlight that developing relatively environmentally friendly synthetic methods in this area is always a great challenge, but also a persistent pursuit. Finally, the scopes, limitations, mechanisms, and existing problems of some reactions are described briefly.
Nineteen diterpenoids, including saldigitin A (1) bearing an unprecedented 10-methylated 6/7/6 carbon ring system, two new icetexanes (2, 3), and two new nor-abietanes (5, 6) were characterized from the roots of Salvia digitaloides. Their structures were elucidated by the analysis of the spectroscopic data, X-ray crystallography, and TDDFT calculations of ECD spectra. The novel architecture of 1 should be biogenetically derived through the cleavage and re-cyclization of the B/C rings from the normal abietane skeleton. Biologically, 1–5 exhibited noticeable inhibitions on Cav3.1 low voltage-gated Ca2+ channel (LVGCC), with IC50 values in the range of 3.43–11.70 µmol/L. They are the first example of diterpenoids with 6/7/6 carbon rings system as Cav3.1 antagonists.
Hypoxia is a typical characteristic of hepatocellular carcinoma (HCC), which causes tremendous obstacles to tumor treatments. Current first-line treatment may further deteriorate tumor hypoxia. For example, Lenvatinib, a receptor tyrosine kinase inhibitor (RTKI), suppresses tumor growth via blocking vascular endothelial growth factor (VEGF) signaling, and can also inhibit angiogenesis, thus limiting oxygen supply to tumor sites. Therefore, alleviating tumor microenvironment (TME) hypoxia holds great potential for enhancing the therapeutic effect of RTKI. Here, nanoparticle-stabilized oxygen microcapsules, a stable and biocompatible oxygen-loaded delivery system, are successfully prepared through interfacial polymerization of polydopamine nanoparticles. The microcapsules with a large loading capacity of oxygen in the core show excellent bioavailability and dispersity, which could effectively improve the hypoxic TME when they serve as oxygen delivery vehicles. Synergetic treatments of Lenvatinib and oxygen microcapsules could induce the transition of “cold tumor” in an immune-suppressed state to “hot tumor” in an immune-activated state by improving tumor hypoxic TME and reducing angiogenesis in HCC. It is revealed that combined treatments of oxygen microcapsules and Lenvatinib could polarize tumor-associated macrophages (TAMs) to anti-tumor M1 cells and activate T cell-mediated anti-tumor immune responses. The results suggest that synergetic therapy using oxygen microcapsules and Lenvatinib could alleviate the hypoxic TME and enhance the therapeutic performance of RTKI, demonstrating a promising anti-tumor strategy for enhanced therapy of HCC.
The conversion of propargylic alcohols and carbon dioxide (CO2) into fine chemicals suffers from issues of harsh reaction conditions and difficult catalyst recovery. To achieve efficient CO2 activation at low energy consumption, a silver-anchored porous aromatic framework catalyst Ag@PAF-DAB with high active phase density and CO2 adsorption capacity was proposed. Since Ag@PAF-DAB has the dual functions of CO2 capture and conversion, propargylic alcohols were completely converted into α-alkylidene cyclic carbonate or α‑hydroxy ketone as high value-added product under atmospheric pressure (CO2, 0.1 MPa) and low silver equivalent (0.5 mol%). Notably, Ag@PAF-DAB exhibited broad substrate diversity, high stability, and excellent reusability. By applying FTIR and GC, the key to green synthetic route of α‑hydroxy ketone was confirmed to lie in the further hydration of α-alkylidene cyclic carbonate.
Cyclin-dependent kinases (CDKs) have become potential targets for treating various diseases, especially cancer. Compound iCDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC (proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of iCDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism. The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore, KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation (IP) assay confirmed a direct interaction between KAT6A and iCDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of iCDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules.
A novel diterpenoid with an unprecedented 5/6/5/7 tetracyclic system, rhodauricanol A (1), five new grayanane-derived diterpenoids, dauricanols A−E (2−6), and five known ones (7−11) were isolated from the flowers of Rhododendron dauricum. Rhodauricanol A (1) possesses a unique 5/6/5/7 tetracyclic ring system featuring a 16-oxa-tetracyclo[11.2.1.01,5.07,13]hexadecane core. Dauricanols A−C (2−4) are the first 1,3-dioxolane conjugates of grayanane diterpenoids and 5-hydroxymethylfurfural and vanillin, respectively, and dauricanols D (5) and E (6) represent the first examples of 6-deoxy-1,5-seco-grayanane diterpenoids. Their structures were determined by spectroscopic methods, quantum chemical calculation including 13C NMR-DP4+ analysis and ECD calculation, and single-crystal X-ray diffraction analysis. Plausible biosynthetic pathways for 1−4 were proposed. All the isolates showed significant analgesic activities, and dauricanols B (3) and C (4) showed more potent analgesic activities than the positive control, morphine.
Computed tomography (CT) is one of the most commonly used non-invasive clinical imaging modalities to predict, diagnose and treat the disease. Iodinated contrast media (ICM) is a form of intravenous radiocontrast agent containing iodine, which enhances the visibility of hollow tissue structures in medical CT imaging. ICM may cause allergic reactions, contrast-induced nephropathy, hyperthyroidism and possibly metformin accumulation. It is significant to find out the risk factors, pathogenesis, diagnosis, prevention, and treatment of adverse reactions caused by ICM. Revealing the changes of the lipid droplets (LDs) viscosity in pathophysiological processes such as cancer and iodined contrast media induced adverse reaction is not only important for monitoring the occurrence and development of some pathophysiological processes but also vital for the deep insight of the biological effects of LDs in these pathophysiological processes. A lipid droplets targeted fluorescent probe DN-1 was devised to sense cellular viscosity alteration with high selectivity and sensitivity, which was applied to distinguish cancer cells and normal cells and reveal viscosity changes during iodined CT contrast media treatment.
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