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  1. Article: Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide-Alkyne Cycloaddition Reactions.

    Timmers, Matt / Kipper, Andi / Frey, Raphael / Notermans, Stef / Voievudskyi, Maksym / Wilson, Claire / Hentzen, Nina / Ringle, Michael / Bovino, Clara / Stump, Bernhard / Rijcken, Cristianne J F / Vermonden, Tina / Dijkgraaf, Ingrid / Liskamp, Rob

    Pharmaceuticals (Basel, Switzerland)

    2023  Volume 16, Issue 8

    Abstract: The recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide-alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of ... ...

    Abstract The recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide-alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of TMTHSI-based compounds via three aspects: (1) large-scale production, (2) unique stability in acidic conditions and its subsequent use in peptide synthesis, and (3) the functionalization of antibodies. Here, it is shown that (1) scale-up is achieved on a scale of up to 100 g. (2) TMTHSI is remarkably stable against TFA allowing for the site-specific functionalization of peptides on resin. Finally, (3) the functionalization of an antibody with a model payload is very efficient, with antibody conjugation demonstrating more beneficial features such as a high yield and limited hydrophobicity as compared to other alkyne reagent conjugates. These results illustrate the high potential of TMTHSI for diverse bioconjugation applications, with production already being GMP-compatible and a highly efficient conversion resulting in attractive costs of goods.
    Language English
    Publishing date 2023-08-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph16081155
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Synthesis of Antibiotics.

    Kalesse, Markus / Böhm, Andreas / Kipper, Andi / Wandelt, Vanessa

    Current topics in microbiology and immunology

    2016  Volume 398, Page(s) 419–445

    Abstract: The synthesis of β-lactams, tetracyclines, and erythromycins as three of the major families of antibiotics will be described herein. We will describe why these antibiotics were the ultimate synthetic targets in the past and how modern synthetic organic ... ...

    Abstract The synthesis of β-lactams, tetracyclines, and erythromycins as three of the major families of antibiotics will be described herein. We will describe why these antibiotics were the ultimate synthetic targets in the past and how modern synthetic organic chemistry has evolved to address these challenges with new, improved strategies and methods. An additional aspect we would like to highlight here is the fact that these first syntheses had to be particularly creative as most of the modern synthetic methods were not available at that time, or were developed in the course of these syntheses.
    MeSH term(s) Anti-Bacterial Agents/chemical synthesis ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/history ; Anti-Bacterial Agents/pharmacology ; Bacteria/drug effects ; History, 20th Century ; History, 21st Century ; Molecular Structure
    Chemical Substances Anti-Bacterial Agents
    Language English
    Publishing date 2016
    Publishing country Germany
    Document type Historical Article ; Journal Article ; Review
    ISSN 0070-217X
    ISSN 0070-217X
    DOI 10.1007/82_2016_502
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  3. Article ; Online: Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain-A new treatment strategy for neonatal seizures?

    Theilmann, Wiebke / Brandt, Claudia / Bohnhorst, Bettina / Winstroth, Anne-Mieke / Das, Anibh Martin / Gramer, Martina / Kipper, Andi / Kalesse, Markus / Löscher, Wolfgang

    Epilepsia

    2020  Volume 62, Issue 1, Page(s) 269–278

    Abstract: Objectives: The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ-aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing ... ...

    Abstract Objectives: The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ-aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N-dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB.
    Methods: In the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats.
    Results: Serum from 1- to 2-day-old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide.
    Significance: These data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add-on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures.
    MeSH term(s) Animals ; Animals, Newborn ; Brain/enzymology ; Brain/metabolism ; Bumetanide/metabolism ; Esterases ; Esters/metabolism ; Female ; Humans ; Infant, Newborn ; Male ; Prodrugs/metabolism ; Rats ; Serum/enzymology ; Serum/metabolism
    Chemical Substances Esters ; Prodrugs ; Bumetanide (0Y2S3XUQ5H) ; Esterases (EC 3.1.-)
    Language English
    Publishing date 2020-11-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 216382-2
    ISSN 1528-1167 ; 0013-9580
    ISSN (online) 1528-1167
    ISSN 0013-9580
    DOI 10.1111/epi.16746
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  4. Article ; Online: Inhibition of Histone Deacetylases 1, 2, and 3 Enhances Clearance of Cholesterol Accumulation in Niemann-Pick C1 Fibroblasts.

    Cruz, Dana L / Pipalia, Nina / Mao, Shu / Gadi, Deepti / Liu, Gang / Grigalunas, Michael / O'Neill, Matthew / Quinn, Taylor R / Kipper, Andi / Ekebergh, Andreas / Dimmling, Alexander / Gartner, Carlos / Melancon, Bruce J / Wagner, Florence F / Holson, Edward / Helquist, Paul / Wiest, Olaf / Maxfield, Frederick R

    ACS pharmacology & translational science

    2021  Volume 4, Issue 3, Page(s) 1136–1148

    Abstract: Niemann-Pick disease type C1 (NPC1) is a rare genetic cholesterol storage disorder caused by mutations in ... ...

    Abstract Niemann-Pick disease type C1 (NPC1) is a rare genetic cholesterol storage disorder caused by mutations in the
    Language English
    Publishing date 2021-05-27
    Publishing country United States
    Document type Journal Article
    ISSN 2575-9108
    ISSN (online) 2575-9108
    DOI 10.1021/acsptsci.1c00033
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  5. Article ; Online: Corrigendum to "Bumepamine, a brain-permeant benzylamine derivative of bumetanide, does not inhibit NKCC1 but is more potent to enhance phenobarbital's antiseizure efficacy" [Neuropharmacology 143 (2018) 186-204].

    Brandt, Claudia / Seja, Patricia / Töllner, Kathrin / Römermann, Kerstin / Hampel, Philip / Kalesse, Markus / Kipper, Andi / Feit, Peter W / Lykke, Kasper / Toft-Bertelsen, Trine Lisberg / Paavilainen, Pauliina / Spoljaric, Inkeri / Puskarjov, Martin / MacAulay, Nanna / Kaila, Kai / Löscher, Wolfgang

    Neuropharmacology

    2018  Volume 143, Page(s) 349–350

    Language English
    Publishing date 2018-10-19
    Publishing country England
    Document type Journal Article ; Published Erratum
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2018.10.012
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  6. Article ; Online: Bumepamine, a brain-permeant benzylamine derivative of bumetanide, does not inhibit NKCC1 but is more potent to enhance phenobarbital's anti-seizure efficacy.

    Brandt, Claudia / Seja, Patricia / Töllner, Kathrin / Römermann, Kerstin / Hampel, Philip / Kalesse, Markus / Kipper, Andi / Feit, Peter W / Lykke, Kasper / Toft-Bertelsen, Trine Lisberg / Paavilainen, Pauliina / Spoljaric, Inkeri / Puskarjov, Martin / MacAulay, Nanna / Kaila, Kai / Löscher, Wolfgang

    Neuropharmacology

    2018  Volume 143, Page(s) 186–204

    Abstract: Based on the potential role of Na-K-Cl cotransporters (NKCCs) in epileptic seizures, the loop diuretic bumetanide, which blocks the NKCC1 isoforms NKCC1 and NKCC2, has been tested as an adjunct with phenobarbital to suppress seizures. However, because of ...

    Abstract Based on the potential role of Na-K-Cl cotransporters (NKCCs) in epileptic seizures, the loop diuretic bumetanide, which blocks the NKCC1 isoforms NKCC1 and NKCC2, has been tested as an adjunct with phenobarbital to suppress seizures. However, because of its physicochemical properties, bumetanide only poorly penetrates through the blood-brain barrier. Thus, concentrations needed to inhibit NKCC1 in hippocampal and neocortical neurons are not reached when using doses (0.1-0.5 mg/kg) in the range of those approved for use as a diuretic in humans. This prompted us to search for a bumetanide derivative that more easily penetrates into the brain. Here we show that bumepamine, a lipophilic benzylamine derivative of bumetanide, exhibits much higher brain penetration than bumetanide and is more potent than the parent drug to potentiate phenobarbital's anticonvulsant effect in two rodent models of chronic difficult-to-treat epilepsy, amygdala kindling in rats and the pilocarpine model in mice. However, bumepamine suppressed NKCC1-dependent giant depolarizing potentials (GDPs) in neonatal rat hippocampal slices much less effectively than bumetanide and did not inhibit GABA-induced Ca
    MeSH term(s) Animals ; Anticonvulsants/chemical synthesis ; Anticonvulsants/chemistry ; Anticonvulsants/pharmacokinetics ; Anticonvulsants/pharmacology ; Benzylamines/chemical synthesis ; Benzylamines/chemistry ; Benzylamines/pharmacokinetics ; Benzylamines/pharmacology ; Brain/drug effects ; Brain/metabolism ; Bumetanide/analogs & derivatives ; Bumetanide/chemistry ; Bumetanide/pharmacokinetics ; Bumetanide/pharmacology ; Drug Evaluation, Preclinical ; Drug Synergism ; Epilepsy/drug therapy ; Epilepsy/metabolism ; Female ; Mice ; Oocytes ; Phenobarbital/pharmacokinetics ; Phenobarbital/pharmacology ; Rats, Wistar ; Seizures/drug therapy ; Seizures/metabolism ; Sodium Potassium Chloride Symporter Inhibitors/chemistry ; Sodium Potassium Chloride Symporter Inhibitors/pharmacokinetics ; Sodium Potassium Chloride Symporter Inhibitors/pharmacology ; Solute Carrier Family 12, Member 2/metabolism ; Tissue Culture Techniques ; Xenopus laevis
    Chemical Substances Anticonvulsants ; Benzylamines ; Bumepamine ; Sodium Potassium Chloride Symporter Inhibitors ; Solute Carrier Family 12, Member 2 ; Bumetanide (0Y2S3XUQ5H) ; Phenobarbital (YQE403BP4D)
    Language English
    Publishing date 2018-09-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2018.09.025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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