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| Book/Dissertation / PhD Thesis | FZJ-2026-02859 |
2026
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
Jülich
ISBN: 978-3-95806-931-2
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Please use a persistent id in citations: urn:nbn:de:0001-2608111317481.344039437814 doi:10.34734/FZJ-2026-02859
Abstract: The potential of natural products as a source of new drug candidates is attributable to their versatile biological properties. A proven means of modulating the pharmacokinetic properties and biological activities of these compounds is their derivatisation. Notable natural products in this regard include the indole alkaloids deoxyviolacein, physostigmine and lansai-B, though the number of derivatives of these compounds that have been described remains limited. In this study, mutasynthetic, chemoenzymatic, and transition metal-based strategies were applied to gain access to new derivatives of these three natural products. In collaboration with Dr. Anita Loeschcke and Dr. Robin Weihmann, new Pseudomonas putida KT2440 strains were developed to produce 7-chlorinated deoxyviolacein derivatives by mutasynthesis. To this end, the bacteria's tryptophan production was disrupted and a modified gene cluster was genomically integrated to generate a selective production and a long-term stable mutasynthesis platform. Furthermore, the targeted natural product derivatives were produced by total synthesis as a reference, and the mutasynthesis synthons were provided chemically and enzymatically. In addition, the methyltransferase PsmD from Streptomyces albulus was used on a preparative scale in collaboration with M. Sc. Diana Amariei to synthesise a biologically active precursor of physostigmine in an enantioselective manner. The attachment of various functional groups by iridium-catalysed borylation provided further insights into the substratespectrum of the methyltransferase and resulted in the characterisation of new biologically active hexahydropyrrolo[2,3-b]indole compounds. The introduction of a 7-bromo substituent has been shown to enable the possibility of further derivatisation at a late stage in the synthesis, thereby rendering numerous other functional groups accessible.The synthetic value of a methyltransferase was further emphasised through a collaboration with M. Sc. Mona Haase, establishing a new chemoenzymatic total synthesis of lansai-B. For this purpose, a methyltransferase from Streptomyces griseoviridis was employed in a preparative manner to obtain the central hexahydropyrrolo[2,3-b]indole structural motif enantioselectively. The required diketopiperazine substrates were provided enantioselectively using an optimised tryptophan-synthase from Pyrococcus furiosus, and the synthesis of the natural product was completed by a Suzuki-Miyaura cross-coupling and a chemical N-methylation. Furthermore, a substantial number of additional derivatives of the enzyme substrate were produced and, where applicable, utilised in the ensuing synthesis towards lansai-B derivatives. The produced substance library was also screened for its cytotoxic properties against various cell lines by the collaborators of Dr. Nicole Teusch's research group. The study revealed that certain of these novel molecules exhibited higher activities than the naturally occurring compounds. In addition, some of the compounds produced can be used in further studies to gain insights into the biosynthesis of lansai-B.
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