Biosynthetic and synthetic studies of the fungal metabolite galiellalactone
Author
Summary, in English
Galiellalactone is a fungal metabolite found in the basidiomycetes Galiella rufa and the unidentified strain A111-95. It has been shown to possess promising activities as an inhibitor of the IL-6 mediated STAT3 signaling in HepG2 cells. Targeting this pathway is very important when it comes to understanding intracellular signaling and also for developing drugs for treating diseases associated with the deregulation of IL-6 signaling and STAT3 activation. To initiate a structure-activity relationship study, an enantiodivergent synthesis of both enantiomers of galiellalactone starting from R-(+)-pulegone was devised and implemented. This led to the revision of the previously reported absolute configuration. A series of derivatives and analogs of the parent natural product was prepared and their STAT3 inhibiting activities were assayed. None showed more potency than galiellalactone itself. We proposed that galiellalactone acts as a Michael acceptor with the receptor and that there are certain specific interactions but these could not be determined.
The biosynthetic pathway to galiellalactone includes the key intermediates pregaliellalactone and desoxygaliellalactone which we synthesized in both labeled and enantiomerically pure form. Feeding experiments were conducted with active mycelium from Galiella rufa, which showed that pregaliellalactone, was cyclised to desoxygaliellalactone in the first biocatalyzed inverse electron demand intramolecular Diels-Alder reaction known in Nature. The cyclisation was spontaneous in water but in the presence of active mycelium an increase in the rate of the cyclisation was observed with the natural enantiomer. The final hydroxylation proceeded only in the presence of mycelium and was highly enantioselective.
The biosynthetic pathway to galiellalactone includes the key intermediates pregaliellalactone and desoxygaliellalactone which we synthesized in both labeled and enantiomerically pure form. Feeding experiments were conducted with active mycelium from Galiella rufa, which showed that pregaliellalactone, was cyclised to desoxygaliellalactone in the first biocatalyzed inverse electron demand intramolecular Diels-Alder reaction known in Nature. The cyclisation was spontaneous in water but in the presence of active mycelium an increase in the rate of the cyclisation was observed with the natural enantiomer. The final hydroxylation proceeded only in the presence of mycelium and was highly enantioselective.
Department/s
Publishing year
2002
Language
English
Document type
Dissertation
Publisher
Bioorganic Chemistry, Lund University
Topic
- Organic Chemistry
Keywords
- Biotechnology
- Bioteknik
- Organisk kemi
- Organic chemistry
- enzyme
- mycelium
- intramolecular Diels-Alder reaction
- Diels-Alderase
- asymmetric synthesis
- biosynthesis
- total synthesis
- STAT3 inhibition
- galiellalactone
- fungal metabolite
Status
Published
Supervisor
- [unknown] [unknown]
ISBN/ISSN/Other
- ISBN: 91-628-5107-1
- ISRN: LUTKDH/(TKOK-1052)/1-102/(2002)
Defence date
1 March 2002
Defence time
13:15
Defence place
Chemical Center K:B, Lund
Opponent
- J.W. Scheeren (Prof)