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Biosynthetic and synthetic studies of the fungal metabolite galiellalactone

Johansson, Martin H LU (2002)
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Prof Scheeren, J.W., Department of Organic Chemistry, University of Nijmegen, Netherlands
organization
publishing date
type
Thesis
publication status
published
subject
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
pages
102 pages
publisher
Bioorganic Chemistry, Lund University
defense location
Chemical Center K:B, Lund
defense date
2002-03-01 13:15
external identifiers
  • Other:ISRN: LUTKDH/(TKOK-1052)/1-102/(2002)
ISBN
91-628-5107-1
language
English
LU publication?
yes
id
a46fdfb0-d410-40d9-95cc-7f2fcce4421d (old id 464398)
date added to LUP
2007-10-14 15:30:22
date last changed
2016-09-19 08:45:09
@misc{a46fdfb0-d410-40d9-95cc-7f2fcce4421d,
  abstract     = {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.<br/><br>
<br/><br>
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.},
  author       = {Johansson, Martin H},
  isbn         = {91-628-5107-1},
  keyword      = {Biotechnology,Bioteknik,Organisk kemi,Organic chemistry,enzyme,mycelium,intramolecular Diels-Alder reaction,Diels-Alderase,asymmetric synthesis,biosynthesis,total synthesis,STAT3 inhibition,galiellalactone,fungal metabolite},
  language     = {eng},
  pages        = {102},
  publisher    = {ARRAY(0xc8a95f0)},
  title        = {Biosynthetic and synthetic studies of the fungal metabolite galiellalactone},
  year         = {2002},
}