Galiellalactone Synthetic Studies
Författare
Summary, in 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 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.
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.
Avdelning/ar
Publiceringsår
2015
Språk
Engelska
Dokumenttyp
Doktorsavhandling
Förlag
CAS
Ämne
- Organic Chemistry
Nyckelord
- natural product
- galiellalactone
- prostate cancer
- STAT3.
Status
Published
Handledare
ISBN/ISSN/Övrigt
- ISBN: 978-91-7422-423-8
Försvarsdatum
18 december 2015
Försvarstid
09:30
Försvarsplats
Lecture hall F, Kemicentrum, Getingevägen 60, Lund University, Faculty of Engineering LTH, Lund
Opponent
- Fredrik Almqvist (Prof.)