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.
|Award date||2015 Dec 18|
|Publication status||Published - 2015|
Bibliographical noteDefence details
Place: Lecture hall F, Kemicentrum, Getingevägen 60, Lund University, Faculty of Engineering LTH, Lund
Name: Almqvist, Fredrik
Affiliation: Umeå University
The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240), External organization(s) (LUR000040)
Subject classification (UKÄ)
- Organic Chemistry
- natural product
- prostate cancer