Manuel Langer

Disputas - Manuel Langer

Master of science Manuel Langer will on August 30th at 12.15 publically defend his PhD degree in science.

Title of the PhD thesis:

"Marine natural product inspired synthesis towards new antimicrobial and antifouling agents"

Abstract:

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.

The thesis is published and available in Munin

Supervisors

  • Professor Annette Bayer, IK, UiT (main supervisor)
  • Vice-dean Morten Bøhmer Strøm, IFA, UiT (Co-supervisor)
  • Dr. scient. Klara Stensvåg, NFH, UiT (Co-supervisor)

Evaluation committee

  • Prof. Nathaniel Martin, Institute of Biology Leiden (IBL), Leiden University, Nederland (1. Opponent)
  • Prof. Yngve Stenstrøm, NMBU, Fakultet for kjemi, bioteknologi og matvitenskap (2. Opponent)
  • Post Dr. Anna Luisa Warnke, IK, UiT (internt medlem og leder av bedømmelseskomiteen)

Leader of the defense: Prof. Hanna-Kirsti Schrøder Leiros, Institutt for kjemi, Det naturvitenskapelige fakultet, UiT

Links to the trial lecture and defense will be possible to open when the live stream begins. If you haven`t clicked the link to the folder before it begins, refresh the web browser for them to become visible. If you have clicked the link to the trial lecture or defense before it has started, it will open automatically when the stream begins. 

The trial lecture starts at 10.15 august 30th

Trial lecture

The defense starts at 12.15 august 30th

Defense

Når: 30.08.22 kl 12.15–16.00
Hvor: Teknobygget auditorium 1.022
Sted: Digitalt, Tromsø
Målgruppe: Ansatte, Studenter, Gjester / eksterne, Inviterte
Kontakt: Eirik Derås Verlo
E-post: eve012@uit.no
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