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Novel biologically active compounds by semisynthesis with fungal metabolites

Eriksson Bajtner, Johan LU (2004)
Abstract
Natural products have been shown to be an important source of novel compounds for the development of new drugs and pesticides. However, many biologically active natural products contain reactive functionalities that make them toxic. By modifying such reactive compounds chemically it is possible to make use of the reactivity to form novel "natural product-like" compounds and at the same time reduce their unselective reactivity. This requires that the compound in question is readily available in sufficient quantities from natural sources or can be synthesised. The chemical transformations that can be used depend on the functionalities present in the natural product, and it is often possible to select reactions that introduce new... (More)
Natural products have been shown to be an important source of novel compounds for the development of new drugs and pesticides. However, many biologically active natural products contain reactive functionalities that make them toxic. By modifying such reactive compounds chemically it is possible to make use of the reactivity to form novel "natural product-like" compounds and at the same time reduce their unselective reactivity. This requires that the compound in question is readily available in sufficient quantities from natural sources or can be synthesised. The chemical transformations that can be used depend on the functionalities present in the natural product, and it is often possible to select reactions that introduce new functionalities that are known to be associated with certain biological activities. In addition, if it is desired, the transformation should introduce one or several components that can be varied, in order to facilitate the preparation of small libraries of compounds. In this work the fungal metabolites podoscyphic acid, an oxidised fatty acid derivative with 16 carbons, and isovelleral, a marasmane sesquiterpene, have been used. Both compounds are available from their respective fungus, but to facilitate the access to the former compound a new and efficient synthesis of podoscyphic acid was developed. A number of transformations of podoscyphic acid was investigated, but eventually its reaction with enaminoesters to form tetrahydro-pyridines, and with 1,2-diaminoarenes to form quinoxalines were selected for more systematic studies. Isovelleral, containing a 1,4-dialdehyde moiety, was used in the classical Robinson-Schöpf-reaction, yielding tropinone derivatives. The products of these transformations have been evaluated in various biological assays, which were conducted by collaborators at the University of Kaiserslautern. The tetrahydropyridines were found to be potent inhibitors of the inducible TNF-a promoter activity in T cells, making them potentially interesting to use as tools to study molecular events during for instance inflammation, while the tropinones interfered with germination of conidia and appressorium formation in germinating conidia of the rice blast fungus Magnaporthe grisea. Even if the products do not turn out to be useful as drugs or pesticides, they will certainly contribute to our understanding of molecular pathways involved in inflammation and germination as well as facilitate new and more thorough investigations (Less)
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author
opponent
  • Docent Mårtensson, Jerker, Göteborg, Chalmers
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Organisk kemi, Organic chemistry, bioactive compounds., isovelleral, podoscyphic acid, Natural products, semisynthesis
pages
100 pages
publisher
Department of Bioorganic Chemistry, Lund University
defense location
Kemicentrum, Room K:B, Lund Institute of Technology
defense date
2004-04-23 13:30
ISBN
91-628-6033-X
language
English
LU publication?
yes
id
636645b4-a613-4c1d-b3d7-bac5d9df6bc3 (old id 466958)
date added to LUP
2007-09-25 20:41:44
date last changed
2016-09-19 08:45:08
@phdthesis{636645b4-a613-4c1d-b3d7-bac5d9df6bc3,
  abstract     = {Natural products have been shown to be an important source of novel compounds for the development of new drugs and pesticides. However, many biologically active natural products contain reactive functionalities that make them toxic. By modifying such reactive compounds chemically it is possible to make use of the reactivity to form novel "natural product-like" compounds and at the same time reduce their unselective reactivity. This requires that the compound in question is readily available in sufficient quantities from natural sources or can be synthesised. The chemical transformations that can be used depend on the functionalities present in the natural product, and it is often possible to select reactions that introduce new functionalities that are known to be associated with certain biological activities. In addition, if it is desired, the transformation should introduce one or several components that can be varied, in order to facilitate the preparation of small libraries of compounds. In this work the fungal metabolites podoscyphic acid, an oxidised fatty acid derivative with 16 carbons, and isovelleral, a marasmane sesquiterpene, have been used. Both compounds are available from their respective fungus, but to facilitate the access to the former compound a new and efficient synthesis of podoscyphic acid was developed. A number of transformations of podoscyphic acid was investigated, but eventually its reaction with enaminoesters to form tetrahydro-pyridines, and with 1,2-diaminoarenes to form quinoxalines were selected for more systematic studies. Isovelleral, containing a 1,4-dialdehyde moiety, was used in the classical Robinson-Schöpf-reaction, yielding tropinone derivatives. The products of these transformations have been evaluated in various biological assays, which were conducted by collaborators at the University of Kaiserslautern. The tetrahydropyridines were found to be potent inhibitors of the inducible TNF-a promoter activity in T cells, making them potentially interesting to use as tools to study molecular events during for instance inflammation, while the tropinones interfered with germination of conidia and appressorium formation in germinating conidia of the rice blast fungus Magnaporthe grisea. Even if the products do not turn out to be useful as drugs or pesticides, they will certainly contribute to our understanding of molecular pathways involved in inflammation and germination as well as facilitate new and more thorough investigations},
  author       = {Eriksson Bajtner, Johan},
  isbn         = {91-628-6033-X},
  keyword      = {Organisk kemi,Organic chemistry,bioactive compounds.,isovelleral,podoscyphic acid,Natural products,semisynthesis},
  language     = {eng},
  pages        = {100},
  publisher    = {Department of Bioorganic Chemistry, Lund University},
  school       = {Lund University},
  title        = {Novel biologically active compounds by semisynthesis with fungal metabolites},
  year         = {2004},
}