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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
supervisor
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 13:15:00
external identifiers
  • other:ISRN: LUTKDH/(TKOK-1052)/1-102/(2002)
ISBN
91-628-5107-1
language
English
LU publication?
yes
additional info
Article: I. Martin Johansson, Bärbel Köpcke, Heidrun Anke and Olov SternerBiologically active secondary metabolites from the ascomycete A111-95: 2. Structure elucidationJournal of Antibiotics, in pressII. Martin Johansson and Olov SternerSynthesis of (+)-galiellalactone. Absolute configuration of galiellalactoneOrganic Letters 2001, 3, 2843-2845III. Martin Johansson, Bärbel Köpcke, Heidrun Anke and Olov SternerSynthesis of (-)-pregaliellalactone, conversion of (-)-pregaliellalactone to (-)-galiellalactone by mycelia of Galiella rufaTetrahedron, submittedIV. Martin Johansson, Bärbel Köpcke, Heidrun Anke and Olov SternerCyclisation of (-)-pregaliellalactone in the fungus Galiella rufasubmittedV. Martin Johansson, Bärbel Köpcke, Heidrun Anke and Olov SternerThe hydroxylation of desoxygaliellalactone by mycelia of Galiella rufain manuscriptVI. Martin Johansson and Olov SternerSynthesis of (-)-galiellalactoneTetrahedron Letters, submitted 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)
id
a46fdfb0-d410-40d9-95cc-7f2fcce4421d (old id 464398)
date added to LUP
2016-04-04 11:19:43
date last changed
2018-11-21 21:04:07
@phdthesis{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},
  language     = {eng},
  publisher    = {Bioorganic Chemistry, Lund University},
  school       = {Lund University},
  title        = {Biosynthetic and synthetic studies of the fungal metabolite galiellalactone},
  year         = {2002},
}