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Galiellalactone Synthetic Studies

Escobar, Zilma LU (2015)
Abstract (Swedish)
Popular Abstract in English

Prostate cancer is one of the most common causes of death for men. This disease can be detected at different stages and if it is detected at an initial stage there are many therapies to choose from. However, if it is detected at an advanced stage the options are reduced and most of the treatments are aggressive in an effort to extend the patient’s life. The most common treatment is hormone-based but as most hormone dependent cancers it becomes resistant to treatment. At this stage it is called castration-resistant prostate cancer (CRPC) since it does not respond to chemical or surgical castration.

With the urgent need to find new cures, science has again resorted to natural products. In... (More)
Popular Abstract in English

Prostate cancer is one of the most common causes of death for men. This disease can be detected at different stages and if it is detected at an initial stage there are many therapies to choose from. However, if it is detected at an advanced stage the options are reduced and most of the treatments are aggressive in an effort to extend the patient’s life. The most common treatment is hormone-based but as most hormone dependent cancers it becomes resistant to treatment. At this stage it is called castration-resistant prostate cancer (CRPC) since it does not respond to chemical or surgical castration.

With the urgent need to find new cures, science has again resorted to natural products. In a search for compounds with anticancer activity galiellalactone was found, a natural product that is produced by a fungus. As for many other compounds that come from nature, the relative small amounts that can be obtained from the natural source are limiting more advanced biological studies. However, as chemists we can synthesize not only the natural product but also derivatives and analogs that can be used to elucidate the mechanism of action at the molecular level.

The work presented in this thesis is built on what was previously known about galiellalactone and its analogs. Herein we present novel galiellalactone analogs that allowed us to evaluate it as a therapeutic agent for treatment of CRPC. This work includes the identification of the target protein, which makes it easier for future design of better analogs and the development of a semi-synthetic route to obtain analogs in large scale. Semi-synthesis indicates that some parts of the chemistry is done by utilizing the biosynthetic machinery in an organism’s traditional methods while others are synthetic transformations. We also designed and synthesized prodrugs of galiellalactone. A prodrug is an inactive version of an active principle that gets converted/transformed in the body to the active form. By using the prodrug approach the active compound’s physical properties can be changed to improve for example its distribution and absorption in the body. (Less)
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof. Almqvist, Fredrik, Umeå University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
natural product, galiellalactone, prostate cancer, STAT3.
pages
74 pages
publisher
CAS
defense location
Lecture hall F, Kemicentrum, Getingevägen 60, Lund University, Faculty of Engineering LTH, Lund
defense date
2015-12-18 09:30
ISBN
978-91-7422-423-8
language
English
LU publication?
yes
id
5ffef097-fcc5-4341-8a11-163ed1f2346e (old id 8228727)
date added to LUP
2015-11-24 07:30:25
date last changed
2016-09-19 08:45:14
@misc{5ffef097-fcc5-4341-8a11-163ed1f2346e,
  abstract     = {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.},
  author       = {Escobar, Zilma},
  isbn         = {978-91-7422-423-8},
  keyword      = {natural product,galiellalactone,prostate cancer,STAT3.},
  language     = {eng},
  pages        = {74},
  publisher    = {ARRAY(0xb8fde28)},
  title        = {Galiellalactone Synthetic Studies},
  year         = {2015},
}