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Galiellalactone Synthetic Studies

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Author

Summary, in English

In search for remedies and treatments, science has recurred to Mother Nature. This is where galiellalactone was found, a fungal metabolite isolated from Galiella rufa in 1990. Since then chemists and biologists have been studying its properties and found it to be a potential candidate against castration-resistance prostate cancer (CRPC). The development of a new drug requires many studies of the compound and analogs thereof. Our contribution has been to generate new synthetic routes and to synthesize new analogs of galiellalactone with different substitutions in position C-4 and C-7. Among these, two were used as tools to confirm that galiellalactone binds directly to the STAT3 protein and that this binding event prevents the transcription by STAT3. Knowing that STAT3 is the target for galiellalactone, a new computational model revealed C-7b as an interesting position for different substituents. To investigate this, more biological studies in vivo and in vitro were needed and hence more galiellalactone analogs. In order to meet the demands of larger quantities we solved this problem by finding optimal conditions for a fermentation process in large scale. With sufficient amounts of galiellalacton in our hands, we designed semi-synthetic routes starting with two main focuses; to develop prodrugs, and to prepare new analogs focusing on substitutions at positions C-4 and C-7b for QSAR studies. We prepared a number of amine and thiol adducts as potential prodrugs, among these one thiol adduct (GPA512) showed promising results in vivo and in vitro. In parallel, a synthetic route towards desoxygaliellalactam was developed, this product will in a near future be tested for hydroxylation by the fungus. The overall objective of this work has therefore been to contribute to the probing of the potential of galiellalactone as a candidate of a drug for patients suffering from CRPC.

Publishing year

2015

Language

English

Document type

Dissertation

Publisher

CAS

Topic

  • Organic Chemistry

Keywords

  • natural product
  • galiellalactone
  • prostate cancer
  • STAT3.

Status

Published

Supervisor

ISBN/ISSN/Other

  • ISBN: 978-91-7422-423-8

Defence date

18 December 2015

Defence time

09:30

Defence place

Lecture hall F, Kemicentrum, Getingevägen 60, Lund University, Faculty of Engineering LTH, Lund

Opponent

  • Fredrik Almqvist (Prof.)