Pseudo-natural products via Pictet-Spengler reaction and dearomatization
| dc.contributor.advisor | Waldmann, Herbert | |
| dc.contributor.author | Burhop, Annina | |
| dc.contributor.referee | Brunschweiger, Andreas | |
| dc.date.accepted | 2021-02-25 | |
| dc.date.accessioned | 2021-05-27T12:13:12Z | |
| dc.date.available | 2021-05-27T12:13:12Z | |
| dc.date.issued | 2020 | |
| dc.description.abstract | Natural products (NPs) occupy a broad diversity in bioactivity and therefore, serve as a comprehensive inspiration in drug discovery. Many design approaches for small molecule collections are based on NPs while aiming for extending nature’s chemical space to discover unexpected or novel bioactivities. Analogously, the pseudo-NP approach affords novel scaffolds by combining unrelated NP fragments in complexity-generating reactions. A collection of spirocyclic pseudo-NPs was generated via iso-oxa-Pictet-Spengler reaction, for which new conditions were developed. Cheminformatic analysis indicated the pseudo-NPs to cover chemical space sparsely represented by NPs, drugs and drug-like compounds and that they may combine favorable properties of these compound classes. Biological evaluation of indofulvins derived from 2-hydroxyethyl-indoles and the fragment-sized NP griseofulvin in different cell-based assays and the high content cell painting assay revealed them to define a new autophagy inhibitor chemotype that targets mitochondrial respiration. A new level of complexity and diversity was introduced by the dearomatization of indole-containing pseudo-NPs. The ɣ-pyrone annulation was optimized to yield structural diverse indolenines and indolines that show biological differences to their parent compounds in the cell painting assay. Morphological profiling was furthermore employed to identify relevant chemical structures for bioactivity to potentially guide future synthesis of small compound collections. These results suggest that the pseudo-NP concept in combination with the cell painting assay may be able to be used to rationally design new compound classes and therefore, further explore chemical space with biological relevance. | en |
| dc.identifier.uri | http://hdl.handle.net/2003/40200 | |
| dc.identifier.uri | http://dx.doi.org/10.17877/DE290R-22073 | |
| dc.language.iso | en | de |
| dc.subject | Pseudo-Naturstoffe | de |
| dc.subject | Pseudo-natural products | en |
| dc.subject | Pictet-Spengler | en |
| dc.subject | Dearomatization | en |
| dc.subject | Autophagy | en |
| dc.subject | Cell painting | en |
| dc.subject | Morphological profiling | en |
| dc.subject.ddc | 570 | |
| dc.subject.ddc | 540 | |
| dc.subject.rswk | Naturstoffchemie | de |
| dc.subject.rswk | Autophagie | de |
| dc.title | Pseudo-natural products via Pictet-Spengler reaction and dearomatization | en |
| dc.type | Text | de |
| dc.type.publicationtype | doctoralThesis | de |
| dcterms.accessRights | open access | |
| eldorado.secondarypublication | false | de |