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  1. Article ; Online: Significance of Five-Membered Heterocycles in Human Histone Deacetylase Inhibitors.

    Frühauf, Anton / Behringer, Martin / Meyer-Almes, Franz-Josef

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 15

    Abstract: Five-membered heteroaromatic rings, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. The unique physicochemical ... ...

    Abstract Five-membered heteroaromatic rings, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. The unique physicochemical properties and biological effects of five-membered heterocycles have positioned them as key structural motifs in numerous clinically effective drugs. Hence, the exploration of five-ring heterocycles remains an important research area in medicinal chemistry, with the aim of discovering new therapeutic agents for various diseases. This review addresses the incorporation of heteroatoms such as nitrogen, oxygen and sulfur into the aromatic ring of these heterocyclic compounds, enhancing their polarity and facilitating both aromatic stacking interactions and the formation of hydrogen bonds. Histone deacetylases are present in numerous multiprotein complexes within the epigenetic machinery and play a central role in various cellular processes. They have emerged as important targets for cancer, neurodegenerative diseases and other therapeutic indications. In histone deacetylase inhibitors (HDACi's), five-ring heterocycles perform various functions as a zinc-binding group, a linker or head group, contributing to binding activity and selective recognition. This review focuses on providing an up-to-date overview of the different five-membered heterocycles utilized in HDACi motifs, highlighting their biological properties. It summarizes relevant publications from the past decade, offering insights into the recent advancements in this field of research.
    MeSH term(s) Humans ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemistry ; Neoplasms ; Heterocyclic Compounds/pharmacology ; Heterocyclic Compounds/chemistry ; Histone Deacetylases
    Chemical Substances Histone Deacetylase Inhibitors ; Heterocyclic Compounds ; Histone Deacetylases (EC 3.5.1.98)
    Language English
    Publishing date 2023-07-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules28155686
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  2. Article ; Online: Synthesis and Characterization of Reversible Covalent HDAC4 Inhibitors.

    Frühauf, Anton / Wolff, Benjamin / Schweipert, Markus / Meyer-Almes, Franz-Josef

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2589, Page(s) 207–221

    Abstract: Cyanoacrylates define a class of inhibitors which are capable to form a transient covalent bond with a cysteine flanking the binding site, thereby increasing the residence time and prolonging the inhibitory effect on the target protein under ... ...

    Abstract Cyanoacrylates define a class of inhibitors which are capable to form a transient covalent bond with a cysteine flanking the binding site, thereby increasing the residence time and prolonging the inhibitory effect on the target protein under nonequilibrium conditions. Herein, we describe the synthetic access to cyanoacrylate-based HDAC4 inhibitors and the procedures for the characterization of the transient nature of the covalent bond between cyanoacrylates and thiols or cysteines in HDAC4.
    MeSH term(s) Cysteine/metabolism ; Binding Sites ; Cyanoacrylates ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/chemistry
    Chemical Substances Cysteine (K848JZ4886) ; Cyanoacrylates ; Histone Deacetylase Inhibitors
    Language English
    Publishing date 2022-10-18
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2788-4_14
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation.

    Schweipert, Markus / Nehls, Thomas / Frühauf, Anton / Debarnot, Cecilé / Kumar, Adarsh / Knapp, Stefan / Lermyte, Frederik / Meyer-Almes, Franz-Josef

    Protein science : a publication of the Protein Society

    2024  Volume 33, Issue 3, Page(s) e4917

    Abstract: Human histone deacetylase 4 (HDAC4) is a key epigenetic regulator involved in a number of important cellular processes. This makes HDAC4 a promising target for the treatment of several cancers and neurodegenerative diseases, in particular Huntington's ... ...

    Abstract Human histone deacetylase 4 (HDAC4) is a key epigenetic regulator involved in a number of important cellular processes. This makes HDAC4 a promising target for the treatment of several cancers and neurodegenerative diseases, in particular Huntington's disease. HDAC4 is highly regulated by phosphorylation and oxidation, which determine its nuclear or cytosolic localization, and exerts its function through multiple interactions with other proteins, forming multiprotein complexes of varying composition. The catalytic domain of HDAC4 is known to interact with the SMRT/NCOR corepressor complex when the structural zinc-binding domain (sZBD) is intact and forms a closed conformation. Crystal structures of the HDAC4 catalytic domain have been reported showing an open conformation of HDAC4 when bound to certain ligands. Here, we investigated the relevance of this HDAC4 conformation under physiological conditions in solution. We show that proper zinc chelation in the sZBD is essential for enzyme function. Loss of the structural zinc ion not only leads to a massive decrease in enzyme activity, but it also has serious consequences for the overall structural integrity and stability of the protein. However, the Zn
    MeSH term(s) Humans ; Catalytic Domain ; Ligands ; Phosphorylation ; Histone Deacetylases/chemistry ; Zinc
    Chemical Substances Ligands ; Histone Deacetylases (EC 3.5.1.98) ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2024-02-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1106283-6
    ISSN 1469-896X ; 0961-8368
    ISSN (online) 1469-896X
    ISSN 0961-8368
    DOI 10.1002/pro.4917
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3407: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 1: Show issues

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  4. Article ; Online: Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases.

    Frühauf, Anton / Meyer-Almes, Franz-Josef

    Molecules (Basel, Switzerland)

    2021  Volume 26, Issue 17

    Abstract: Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent ...

    Abstract Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.
    MeSH term(s) Animals ; Carrier Proteins/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Humans ; Hydroxamic Acids/metabolism ; Hydroxylamine/metabolism ; Structure-Activity Relationship ; Zinc/metabolism
    Chemical Substances Carrier Proteins ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; zinc-binding protein ; Hydroxylamine (2FP81O2L9Z) ; Histone Deacetylases (EC 3.5.1.98) ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2021-08-25
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules26175151
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  5. Article ; Online: Phosphodiester photo-tethers for the (multi-)cyclic conformational caging of oligonucleotides.

    Müller, Patricia / Seyfried, Patrick / Frühauf, Anton / Heckel, Alexander

    Methods in enzymology

    2019  Volume 624, Page(s) 89–111

    Abstract: The ability to address the function of oligonucleotides with light is highly desirable since they are often used experimentally in the regulation of biological processes that need to be controlled in time, space and activation level. Here we present an ... ...

    Abstract The ability to address the function of oligonucleotides with light is highly desirable since they are often used experimentally in the regulation of biological processes that need to be controlled in time, space and activation level. Here we present an extension of our initial approach of using photo-tethers that force single strands of nucleic acids into a circle, thus making them unable to form a duplex with a complementary DNA- or RNA-strand. Due to the persistence length a single strand can form a circle of, for example, 30 nucleotides, but a duplex cannot. We show that these new photo-tethers can also be easily installed on the phosphodiester backbone. This simplifies the approach considerably and leads to temporarily inhibited oligonucleotides that can only form a duplex after linearization by photoactivation.
    MeSH term(s) Alkynes/chemical synthesis ; Alkynes/chemistry ; Click Chemistry/methods ; Copper/chemistry ; Cyclization ; Light ; Nucleic Acid Conformation ; Oligonucleotides/chemical synthesis ; Oligonucleotides/chemistry ; Organophosphorus Compounds/chemical synthesis ; Organophosphorus Compounds/chemistry ; Photochemical Processes
    Chemical Substances Alkynes ; Oligonucleotides ; Organophosphorus Compounds ; phosphodiester alpha ; phosphoramidite ; Copper (789U1901C5)
    Language English
    Publishing date 2019-05-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1557-7988 ; 0076-6879
    ISSN (online) 1557-7988
    ISSN 0076-6879
    DOI 10.1016/bs.mie.2019.04.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: 3-Chloro-5-Substituted-1,2,4-Thiadiazoles (TDZs) as Selective and Efficient Protein Thiol Modifiers.

    Jänsch, Niklas / Frühauf, Anton / Schweipert, Markus / Debarnot, Cécile / Erhardt, Miriam / Brenner-Weiss, Gerald / Kirschhöfer, Frank / Jasionis, Tomas / Čapkauskaitė, Edita / Zubrienė, Asta / Matulis, Daumantas / Meyer-Almes, Franz-Josef

    Chembiochem : a European journal of chemical biology

    2022  Volume 23, Issue 21, Page(s) e202200417

    Abstract: The study of cysteine modifications has gained much attention in recent years. This includes detailed investigations in the field of redox biology with focus on numerous redox derivatives like nitrosothiols, sulfenic acids, sulfinic acids and sulfonic ... ...

    Abstract The study of cysteine modifications has gained much attention in recent years. This includes detailed investigations in the field of redox biology with focus on numerous redox derivatives like nitrosothiols, sulfenic acids, sulfinic acids and sulfonic acids resulting from increasing oxidation, S-lipidation, and perthiols. For these studies selective and rapid blocking of free protein thiols is required to prevent disulfide rearrangement. In our attempt to find new inhibitors of human histone deacetylase 8 (HDAC8) we discovered 5-sulfonyl and 5-sulfinyl substituted 1,2,4-thiadiazoles (TDZ), which surprisingly show an outstanding reactivity against thiols in aqueous solution. Encouraged by these observations we investigated the mechanism of action in detail and show that these compounds react more specifically and faster than commonly used N-ethyl maleimide, making them superior alternatives for efficient blocking of free thiols in proteins. We show that 5-sulfonyl-TDZ can be readily applied in commonly used biotin switch assays. Using the example of human HDAC8, we demonstrate that cysteine modification by a 5-sulfonyl-TDZ is easily measurable using quantitative HPLC/ESI-QTOF-MS/MS, and allows for the simultaneous measurement of the modification kinetics of seven solvent-accessible cysteines in HDAC8.
    MeSH term(s) Humans ; Sulfhydryl Compounds ; Cysteine/metabolism ; Thiadiazoles/pharmacology ; Tandem Mass Spectrometry ; Sulfenic Acids ; Oxidation-Reduction ; Histone Deacetylases/metabolism ; Repressor Proteins/metabolism
    Chemical Substances Sulfhydryl Compounds ; Cysteine (K848JZ4886) ; Thiadiazoles ; Sulfenic Acids ; HDAC8 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) ; Repressor Proteins
    Language English
    Publishing date 2022-09-27
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2020469-3
    ISSN 1439-7633 ; 1439-4227
    ISSN (online) 1439-7633
    ISSN 1439-4227
    DOI 10.1002/cbic.202200417
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Book: Rebenlandschaft Südtirol

    Kofler, Oswald / Frühauf, Anton

    1984  

    Institution Südtirol
    Author's details mit 260 Aufnahmen von Oswald Kofler und 12 Zeichnungen nach Originalen von Anton Frühauf
    Keywords Weinbau / Bildband ; Südtirol / Bildbände
    Language German
    Size 244 S., 272 Illustrationen, 29 cm
    Publisher Verlagsanstalt Athesia
    Publishing place Bozen
    Publishing country Italy
    Document type Book
    HBZ-ID HT020989758
    ISBN 88-7014-335-X ; 978-88-7014-335-5
    Database Catalogue ZB MED Nutrition, Environment, Agriculture

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    In stock of ZB MED Bonn / Germany

    Shelf markLoan statusLocation
    844/165 order for loan Geschlossenes Magazin (U2)

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