Thai, Nguyen Yen Chi (2022)
Chemoenzymatic Synthesis of Chiral Alcohols Relevant to Pharmaceutical Industry.
Technische Universität Darmstadt
doi: 10.26083/tuprints-00020619
Dissertation, Erstveröffentlichung, Verlagsversion
Kurzbeschreibung (Abstract)
1. From 1987 on, statins have been introduced to the market as cholesterol lowering agents and have, ever since, settled their position as one of the most prescribed drugs for the treatment of cardiovascular diseases. Recent studies have revealed that beyond their lipid lowering properties, statins are also associated with a plethora of biological and pharmacological effects, e. g. anti-inflammatory and immunosuppressive properties. Novel, potent statins that feature structural diversity are therefore highly desirable for further research. Concomitantly, improved synthesis strategies towards easier access to the challenging chiral key motif are furthermore in great demand. Following trending biocatalytic approaches, this work introduces an efficient, green, and facile route for the production of simple statins by employing a novel 2-deoxyribose-5-phosphate aldoldase (DERA) in a sequential aldol addition manner and a novel alcohol dehydrogenase (ADH) for the subsequent regioselective oxidation process. Ultimately, the inhibitory activities of the obtained statins towards HMG-CoA-reductase were assessed and confirmed.
2. Expanding the scope of biocatalysts towards non-natural substrates, by employing novel, engineered, clean, and highly selective enzymes, can offer new and attractive opportunities for the substitution of multi-step chemical pathways for the manufacturing of pharmaceutically relevant intermediates. In this context, ketoreductases are the most commonly employed enzymes in industrial pharmaceutical synthesis. By implementing a highly sensitive, high-throughput assay strategy, the (R)-selective ketoreductase from Lactobacillus brevis (LbKRED) was redesigned towards tolerating a series of non-natural, bulky substrates, including a precursor to the antithrombotic agent ticagrelor.
| Typ des Eintrags: | Dissertation | ||||
|---|---|---|---|---|---|
| Erschienen: | 2022 | ||||
| Autor(en): | Thai, Nguyen Yen Chi | ||||
| Art des Eintrags: | Erstveröffentlichung | ||||
| Titel: | Chemoenzymatic Synthesis of Chiral Alcohols Relevant to Pharmaceutical Industry | ||||
| Sprache: | Englisch | ||||
| Referenten: | Fessner, Prof. Dr. Wolf-Dieter ; Kolmar, Prof. Dr. Harald | ||||
| Publikationsjahr: | 2022 | ||||
| Ort: | Darmstadt | ||||
| Kollation: | xii, 162, 28 Seiten | ||||
| Datum der mündlichen Prüfung: | 31 Januar 2022 | ||||
| DOI: | 10.26083/tuprints-00020619 | ||||
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/20619 | ||||
| Kurzbeschreibung (Abstract): | 1. From 1987 on, statins have been introduced to the market as cholesterol lowering agents and have, ever since, settled their position as one of the most prescribed drugs for the treatment of cardiovascular diseases. Recent studies have revealed that beyond their lipid lowering properties, statins are also associated with a plethora of biological and pharmacological effects, e. g. anti-inflammatory and immunosuppressive properties. Novel, potent statins that feature structural diversity are therefore highly desirable for further research. Concomitantly, improved synthesis strategies towards easier access to the challenging chiral key motif are furthermore in great demand. Following trending biocatalytic approaches, this work introduces an efficient, green, and facile route for the production of simple statins by employing a novel 2-deoxyribose-5-phosphate aldoldase (DERA) in a sequential aldol addition manner and a novel alcohol dehydrogenase (ADH) for the subsequent regioselective oxidation process. Ultimately, the inhibitory activities of the obtained statins towards HMG-CoA-reductase were assessed and confirmed. 2. Expanding the scope of biocatalysts towards non-natural substrates, by employing novel, engineered, clean, and highly selective enzymes, can offer new and attractive opportunities for the substitution of multi-step chemical pathways for the manufacturing of pharmaceutically relevant intermediates. In this context, ketoreductases are the most commonly employed enzymes in industrial pharmaceutical synthesis. By implementing a highly sensitive, high-throughput assay strategy, the (R)-selective ketoreductase from Lactobacillus brevis (LbKRED) was redesigned towards tolerating a series of non-natural, bulky substrates, including a precursor to the antithrombotic agent ticagrelor. |
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| Status: | Verlagsversion | ||||
| URN: | urn:nbn:de:tuda-tuprints-206199 | ||||
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie | ||||
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Organische Chemie |
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| Hinterlegungsdatum: | 25 Mär 2022 11:25 | ||||
| Letzte Änderung: | 28 Mär 2022 06:21 | ||||
| PPN: | |||||
| Referenten: | Fessner, Prof. Dr. Wolf-Dieter ; Kolmar, Prof. Dr. Harald | ||||
| Datum der mündlichen Prüfung / Verteidigung / mdl. Prüfung: | 31 Januar 2022 | ||||
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