Two sides of click chemistry: Synthesis of linkable tomaymycin derivatives as in situ activated drugs and a trimethyl lock/ tetrazine-based click-to-release system

Publikation: Qualifikations-/Studienabschlussarbeit › Dissertation

Autoren

  • Julia Alisa Friederich

Organisationseinheiten

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Details

OriginalspracheEnglisch
QualifikationDoctor rerum naturalium
Gradverleihende Hochschule
Betreut von
  • Mark Brönstrup, Betreuer*in
Datum der Verleihung des Grades20 Apr. 2023
ErscheinungsortHannover
PublikationsstatusVeröffentlicht - 2023

Abstract

Bei der Entwicklung von Arzneimitteln müssen verschiedene Herausforderungen gemeistert werden, unter anderem die Sicherstellung ausreichender Halbwertszeit, zellulärer Permeabilität oder die Vermeidung rascher Resistenzbildung. Als wichtige Lösungsstrategie werden ‚Prodrug‘-Ansätze verfolgt, um den Wirkstoff erst am Zielort zu bilden oder in dort freisetzen. Dabei werden entweder biochemischen Prozesse ausgenutzt oder bioorthogonale Reaktionen, die ein breiteres Spektrum an chemischen Modifikationen ermöglichen. Als bioorthogonale Reaktionen werden alle chemischen Reaktionen bezeichnet, die in lebenden Systemen ablaufen können, ohne die natürlichen biochemischen Prozesse zu stören. Ursprünglich wurden bioorthogonale Reaktionen genutzt, um verschiedene chemische Einheiten miteinander zu verbinden. Neuere Arbeiten beschreiben den sogenannten „Click-to-Release“ Ansatz, der die selektive Spaltung zweier chemischer Einheiten durch eine Click-Reaktion ausgelöst. In dieser Studie wurde die in situ Aktivierung von zwei verknüpfbaren Derivaten basierenden auf dem natürlich vorkommenden DNA Binder Tomaymycin untersucht. Es wurden vier verschiedener Heterodimere basierend auf Tomaymycin Derivaten synthetisiert, wobei verschiedene bioorthogonale Reaktionen als Schlüsselschritt zum Einsatz kamen. Mit Hilfe einer Reihe von komplementären biologischen Methoden, wie Plasmid und Oligonucleotid basierten elektrophoretischen Mobilitätsänderungsanalysen, Hochleistungsflüssigchromatographie mit gekoppelter massenspektrometirscher Analyse, Fluoreszenz basierte thermalen DNA-Denaturierungsstudien, sowie DNase basierten DNA-Protektionsexperimenten, konnte innerhalb dieser Studie die DNA-Bindung sowie die DNA-Vernetzung für neuartige Tomaymycin-basierte Heterodimere nachgewiesen werden. Darüber hinaus wird in dieser Studie über ein neuartiges chemisch aktivierbares, bioorthogonales „Click-to-Release“ System berichtet. Dieses kombiniert das Trimethyl-Lock (TML) System mit der bioorthogonalen inversen Elektronenbedarfs-Diels-Alder-Reaktion (IEDDA) an Vinylethern. Es wurden kinetische Studien durchgeführt, die zeigen, dass die Reaktionsgeschwindigkeit je nach Wahl des Diens (hier ausgewählte Tetrazine), reguliert und justiert werden kann, somit konnte eine 42-fache Steigerung der Reaktionsrate erreicht werden.

Zitieren

Two sides of click chemistry: Synthesis of linkable tomaymycin derivatives as in situ activated drugs and a trimethyl lock/ tetrazine-based click-to-release system. / Friederich, Julia Alisa.
Hannover, 2023. 289 S.

Publikation: Qualifikations-/Studienabschlussarbeit › Dissertation

Download
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abstract = "In drug development various challenges have to be overcome, including ensuring sufficient half-life, cellular permeability, or avoiding rapid development of resistance. Prodrug approaches, i.e., forming or releasing the active drug at the target site, are being pursued as vital strategies to address these challenges. Such strategies either utilize biochemical processes or bioorthogonal reactions, which provide a wider array of chemical modifications. Bioorthogonal reactions refer to any chemical reaction that can occur in living systems without interfering with native biochemical processes. Initially, bioorthogonal reactions were used to link different chemical entities. Contemporary studies describe the so-called {"}click-to-release{"} approach, which allows selective cleavage of two chemical entities triggered by a click reaction. This study explored the in situ activation of two linkable derivatives of the naturally occurring DNA binder tomaymycin. A set of four different tomaymycin-based heterodimers were synthetized utilizing different bioorthogonal reactions as the key step. Using a set of complementary biological evaluation methods, i.e., a plasmid and a oligonucleotide based electrophoretic mobility shift assay, a HPLC-MS assay, a fluorescence based thermal DNA denaturation assay, and a DNase I foot printing assay, this study could prove target binding, i.e., DNA-binding as well as DNA cross-linking for two of the novel tomaymycin based heterodimers. In addition this study reports a novel chemically triggered, bioorthogonal click-to-release system. Herein the trimethyl lock (TML) system is combined with the bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction of a vinyl ether and a tetrazine, thus expanding the scope of the TML system. Kinetic studies were carried out showing that the reaction rate can be controlled and adjusted depending on the choice of diene (here selected tetrazines). Thereby a 42-fold increase in reaction rate could be achieved.",
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N2 - In drug development various challenges have to be overcome, including ensuring sufficient half-life, cellular permeability, or avoiding rapid development of resistance. Prodrug approaches, i.e., forming or releasing the active drug at the target site, are being pursued as vital strategies to address these challenges. Such strategies either utilize biochemical processes or bioorthogonal reactions, which provide a wider array of chemical modifications. Bioorthogonal reactions refer to any chemical reaction that can occur in living systems without interfering with native biochemical processes. Initially, bioorthogonal reactions were used to link different chemical entities. Contemporary studies describe the so-called "click-to-release" approach, which allows selective cleavage of two chemical entities triggered by a click reaction. This study explored the in situ activation of two linkable derivatives of the naturally occurring DNA binder tomaymycin. A set of four different tomaymycin-based heterodimers were synthetized utilizing different bioorthogonal reactions as the key step. Using a set of complementary biological evaluation methods, i.e., a plasmid and a oligonucleotide based electrophoretic mobility shift assay, a HPLC-MS assay, a fluorescence based thermal DNA denaturation assay, and a DNase I foot printing assay, this study could prove target binding, i.e., DNA-binding as well as DNA cross-linking for two of the novel tomaymycin based heterodimers. In addition this study reports a novel chemically triggered, bioorthogonal click-to-release system. Herein the trimethyl lock (TML) system is combined with the bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction of a vinyl ether and a tetrazine, thus expanding the scope of the TML system. Kinetic studies were carried out showing that the reaction rate can be controlled and adjusted depending on the choice of diene (here selected tetrazines). Thereby a 42-fold increase in reaction rate could be achieved.

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