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Nature Communications Aug 2023SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific...
SMNDC1 is a Tudor domain protein that recognizes di-methylated arginines and controls gene expression as an essential splicing factor. Here, we study the specific contributions of the SMNDC1 Tudor domain to protein-protein interactions, subcellular localization, and molecular function. To perturb the protein function in cells, we develop small molecule inhibitors targeting the dimethylarginine binding pocket of the SMNDC1 Tudor domain. We find that SMNDC1 localizes to phase-separated membraneless organelles that partially overlap with nuclear speckles. This condensation behavior is driven by the unstructured C-terminal region of SMNDC1, depends on RNA interaction and can be recapitulated in vitro. Inhibitors of the protein's Tudor domain drastically alter protein-protein interactions and subcellular localization, causing splicing changes for SMNDC1-dependent genes. These compounds will enable further pharmacological studies on the role of SMNDC1 in the regulation of nuclear condensates, gene regulation and cell identity.
Topics: Aptamers, Nucleotide; Biomolecular Condensates; Carbocyanines; Nuclear Speckles; SMN Complex Proteins; Tudor Domain
PubMed: 37587144
DOI: 10.1038/s41467-023-40124-0 -
Toxins Dec 2023Piperine is a plant-derived promising piperamide candidate isolated from the black pepper ( L.). In the last few years, this natural botanical product and its... (Review)
Review
Piperine is a plant-derived promising piperamide candidate isolated from the black pepper ( L.). In the last few years, this natural botanical product and its derivatives have aroused much attention for their comprehensive biological activities, including not only medical but also agricultural bioactivities. In order to achieve sustainable development and improve survival conditions, looking for environmentally friendly pesticides with low toxicity and residue is an extremely urgent challenge. Fortunately, plant-derived pesticides are rising like a shining star, guiding us in the direction of development in pesticidal research. In the present review, the recent progress in the biological activities, mechanisms of action, and structural modifications of piperine and its derivatives from 2020 to 2023 are summarized. The structure-activity relationships were analyzed in order to pave the way for future development and utilization of piperine and its derivatives as potent drugs and pesticides for improving the local economic development.
Topics: Alkaloids; Benzodioxoles; Polyunsaturated Alkamides; Pesticides; Biology
PubMed: 38133200
DOI: 10.3390/toxins15120696 -
Bioconjugate Chemistry Nov 2023The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists... (Review)
Review
The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists to combine molecular subunits as if they were puzzle pieces. Over the last 25 years, the click chemistry toolbox has swelled from the canonical copper-catalyzed azide-alkyne cycloaddition to encompass an array of ligations, including bioorthogonal variants, such as the strain-promoted azide-alkyne cycloaddition and the inverse electron-demand Diels-Alder reaction. Without question, the rise of click chemistry has impacted all areas of chemical and biological science. Yet the unique traits of radiopharmaceutical chemistry have made it particularly fertile ground for this technology. In this update, we seek to provide a comprehensive guide to recent developments at the intersection of click chemistry and radiopharmaceutical chemistry and to illuminate several exciting trends in the field, including the use of emergent click transformations in radiosynthesis, the clinical translation of novel probes synthesized using click chemistry, and the advent of click-based pretargeting.
Topics: Click Chemistry; Radiochemistry; Azides; Radiopharmaceuticals; Cycloaddition Reaction; Alkynes
PubMed: 37737084
DOI: 10.1021/acs.bioconjchem.3c00286 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2023The hydrofluorination of alkynes is an efficient synthetic route to monofluoroalkenes or difluoroalkanes. Both fluorinated motifs have found applications in medicinal... (Review)
Review
The hydrofluorination of alkynes is an efficient synthetic route to monofluoroalkenes or difluoroalkanes. Both fluorinated motifs have found applications in medicinal chemistry and beyond. This review explores the recent advances in the hydrofluorination of diverse alkynes through various activation methods, from classical coinage metal catalysis to metal-free conditions. The range of alkynes goes from the simplest unactivated alkynes to activated ones (ynones and derivatives, ynamides, alkynyl sulfides and sulfones as much as haloalkynes). Regio- and stereoselective methods exists, but there is still room for improvement depending on the type of alkyne.
PubMed: 37458694
DOI: 10.1002/chem.202301896 -
ACS Catalysis Oct 2023Catalytic methodologies that enable the synthesis of complex organic molecules from simple and readily available starting materials represent a goal in modern synthetic... (Review)
Review
Catalytic methodologies that enable the synthesis of complex organic molecules from simple and readily available starting materials represent a goal in modern synthetic chemistry. In particular, multicomponent carboboration reactions that provide stereoselective access to densely functionalized building blocks are particularly valuable to achieve molecular diversity. This Perspective covers the developments in the area of catalytic allylboration of alkynes and highlights the key features that have allowed for the control of the regio-, diastereo-, and enantioselectivity in these transformations.
PubMed: 37822858
DOI: 10.1021/acscatal.3c03015 -
Journal of the American Chemical Society Aug 2023The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic...
The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic compounds and conjugated systems. Halogenated alkyne-containing molecules are known to occur in Nature; however, halogen atom installation on the terminus of an alkyne has not been demonstrated in enzyme catalysis. Herein, we report the discovery and characterization of an alkynyl halogenase in natural product biosynthesis. We show that the flavin-dependent halogenase from the jamaicamide biosynthetic pathway, JamD, is not only capable of terminal alkyne halogenation on a late-stage intermediate en route to the final natural product but also has broad substrate tolerance for simple to complex alkynes. Furthermore, JamD is specific for terminal alkynes over other electron-rich aromatic substrates and belongs to a newly identified family of halogenases from marine cyanobacteria, indicating its potential as a chemoselective biocatalyst for the formation of haloalkynes.
Topics: Halogenation; Halogens; Alkynes; Biological Products; Catalysis
PubMed: 37594919
DOI: 10.1021/jacs.3c05750 -
Chemistry (Weinheim An Der Bergstrasse,... May 2024Visible-light-mediated [2+2] photocycloaddition reaction can be considered an ideal solution due to its green and sustainable properties, and is one of the most...
Visible-light-mediated [2+2] photocycloaddition reaction can be considered an ideal solution due to its green and sustainable properties, and is one of the most efficient methods to synthesize four-membered ring motifs. Although research on the [2+2] photocycloaddition of alkynes is challenging because of the diminished reactivity of alkynes, and the more significant ring strain of the products, remarkable achievements have been made in this field. In this article, we highlight the recent advances in visible-light-mediated [2+2] photocycloaddition reactions of alkynes, with focus on the reaction mechanism and the late-stage synthetic applications. Advances in obtaining cyclobutenes, azetines, and oxetene active intermediates continue to be breakthroughs in this fascinating field of research.
PubMed: 38806409
DOI: 10.1002/chem.202401501 -
Chemphyschem : a European Journal of... Aug 2023The [2+2] cycloaddition - retro-electrocyclization (CA-RE) reaction allows ready synthesis of redox-active donor-acceptor chromophores from an electron-rich alkyne and...
The [2+2] cycloaddition - retro-electrocyclization (CA-RE) reaction allows ready synthesis of redox-active donor-acceptor chromophores from an electron-rich alkyne and electron-poor olefins like tetracyanoethylene (TCNE). The detailed mechanism of the reaction has been subject of both computational and experimental studies. While several studies point towards a stepwise mechanism via a zwitterionic intermediate for the first step, the cycloaddition, the reaction follows neither simple second-order nor first-order kinetics. Recent studies have shown that the kinetics can be understood if an autocatalytic step is introduced in the mechanism, in which complex formation with the donor-substituted tetracyanobutadiene (TCBD) product possibly facilitates nucleophilic attack of the alkyne onto TCNE, generating the zwitterionic intermediate of the CA step. This Concept highlights the convenient use of the "click-like" CA-RE reaction to obtain elaborate donor-acceptor chromophores and the recent mechanistic results.
PubMed: 37232195
DOI: 10.1002/cphc.202300236 -
Organic Letters Nov 2023Cadiot-Chodkiewicz cross-couplings generate an unsymmetric buta-1,3-diyne by way of a Cu(I)-catalyzed coupling between a terminal alkyne and a 1-haloalkyne. Despite...
Cadiot-Chodkiewicz cross-couplings generate an unsymmetric buta-1,3-diyne by way of a Cu(I)-catalyzed coupling between a terminal alkyne and a 1-haloalkyne. Despite their widespread use, Cadiot-Chodkiewicz reactions are plagued by the generation of symmetric buta-1,3-diyne side products, formed through competing: (a) formal reductive homo-coupling of the 1-haloalkyne and (b) oxidative (Glaser-Hay/Eglinton) homo-coupling of the terminal alkyne. To overcome this issue, a large excess of one of the two reacting alkynes is commonly deployed, and difficult separations of cross- and homo-coupled products are often encountered. Here, we demonstrate that the use of ascorbate as a reductant leads to a suppression of these unwanted side reactions, hence permitting excellent yields with a roughly stoichiometric ratio of reactants. The procedure also avoids an inert gas atmosphere and uses a sustainable solvent. A similar approach is effective for cross-couplings involving a Pd(0)/Pd(II) catalytic cycle, with air tolerant Sonogashira couplings also established.
PubMed: 37937958
DOI: 10.1021/acs.orglett.3c03314 -
Cells Nov 2023Cells respond to DNA damage by activating a complex array of signaling networks, which include the AMPK and mTOR pathways. After DNA double-strand breakage, ATM, a core...
Cells respond to DNA damage by activating a complex array of signaling networks, which include the AMPK and mTOR pathways. After DNA double-strand breakage, ATM, a core component of the DNA repair system, activates the AMPK-TSC2 pathway, leading to the inhibition of the mTOR cascade. Recently, we showed that both AMPK and mTOR interact with SMYD3, a methyltransferase involved in DNA damage response. In this study, through extensive molecular characterization of gastrointestinal and breast cancer cells, we found that SMYD3 is part of a multiprotein complex that is involved in DNA damage response and also comprises AMPK and mTOR. In particular, upon exposure to the double-strand break-inducing agent neocarzinostatin, SMYD3 pharmacological inhibition suppressed AMPK cascade activation and thereby promoted the mTOR pathway, which reveals the central role played by SMYD3 in the modulation of AMPK-mTOR signaling balance during cancer cell response to DNA double-strand breaks. Moreover, we found that SMYD3 can methylate AMPK at the evolutionarily conserved residues Lys411 and Lys424. Overall, our data revealed that SMYD3 can act as a bridge between the AMPK and mTOR pathways upon neocarzinostatin-induced DNA damage in gastrointestinal and breast cancer cells.
Topics: Humans; Female; AMP-Activated Protein Kinases; Zinostatin; TOR Serine-Threonine Kinases; DNA Damage; DNA; Breast Neoplasms; Histone-Lysine N-Methyltransferase
PubMed: 37998381
DOI: 10.3390/cells12222644