Marine natural product inspired synthesis towards new antimicrobial and antifouling agents

Natural products (NPs) have been the major source for the development of new small molecule drugs in modern medicine. Despite NPs being so prominent, marine natural products (MNPs) and derivatives thereof are hardly found in clinically approved agents. Therefore, using bioactive MNPs as structural g...

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1. Verfasser: Langer, Manuel Karl
Format: Dissertation
Sprache:eng
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Zusammenfassung:Natural products (NPs) have been the major source for the development of new small molecule drugs in modern medicine. Despite NPs being so prominent, marine natural products (MNPs) and derivatives thereof are hardly found in clinically approved agents. Therefore, using bioactive MNPs as structural guidance for drug development is a largely untapped source. The focus of the presented thesis is on two MNPs, the eusynstyelamides and aspergilone A, showing antimicrobial and anticancer/antifouling activity, respectively, thus targeting pressing health and economical challenges – antimicrobial resistance and marine fouling. Our aim was to investigate if small-molecule amphipathic eusynstyelamide derivatives can mimic the antimicrobial activity of AMPs. Almost 100 mimics of the eusynstyelamides were synthesized and tested for their antimicrobial potency and haemolytic activity. Tetrasubstituted, amphipathic barbiturates and hydantoins were the two main structural classes. Barbiturates were found to deliver the most active structures, whereas hydantoins had a better activity toxicity balance. The most active derivatives exhibited MIC values of 2-8 µg/mL against multi-resistant clinical isolates. Further evaluation and refinement of our lead structures may deliver candidates for pre-clinical evaluation. Aspergilone A exhibits antifouling activity and shows additional selective in vitro cytotoxicity. This dual activity and aspergilone A’s structural resemblance to other NPs sparked our interest. The synthesis of aspergilone A has not been described and we aimed to develop an enantioselective synthetic route towards aspergilone A, with ent-phenol A as a key intermediate, initiating a program to develop antifouling agents. The synthetic efforts led to a stereocontrolled and adaptable synthesis of ent-phenol A, which allows for the construction of all four stereoisomers of the latter without any changes to the protocol. Ent-phenol A was obtained enantiopure in >99% ee and 5% yield over 7 steps. The new approach towards ent-phenol A is paving the way for a future total synthesis of aspergilone A, and related NPs, and subsequent structure-activity relationship studies.