Synthesis of Bioactive Analogues of Marasmane Dialdehydes

Detta är en avhandling från Department of Organic Chemistry Lund University

Sammanfattning: The modification of drugs into pro-drugs is an attractive concept allowing you to tweak the chemical and physical properties of a drug without changing the original structure of the active compound. In principle, any compound possessing a preferred biological activity can be transformed into a pro-drug. Many natural products harbor qualities that are potentially interesting as drugs but difficult to implement per se. The marasmane dialdehydes, isovelleral and marasmic acid are two such compounds which are investigated in thesis. These dialdehydes are secondary metabolites isolated from several different fungi (e.g. isovelleral from Lactarius vellerus and marasmic acid from the Marasminus species). There are many biological characteristics associated with these structures, e.g. antifeedant, antibacterial, antifungal, antitumor, cytotoxic and mutagenic activities. Several total syntheses of both natural products have been presented along with limited efforts to synthetically modify their activities. In this thesis, two analogues of these dialdehydes were prepared to further study the possibility to enhance their activities by synthetically modifying these structures. i.e. altering methylation patterns and changing ring systems. We found that the cytotoxicity of the tridemethylated analogue was between 4 and 11 times higher in our assay in comparison with that of isovelleral, and of the same magnitude as that of most potent commercial anti-tumor agents. Furthermore, we have performed theoretical and experimental investigations into their reactivity and reaction mechanisms. The possibility to transform these novel structures along with the original compounds into potential pro-drugs has been extensively investigated. We have focused our attention to the development of pro-drugs in particular related to cancer and environmentally friendly pesticides. In case of the latter application, promising results have already been shown towards the control of the rice blast disease caused by Magnaporthe grisea. Thus, this work expose a novel platform for targeting diseases using derivatives of isovelleral and marasmic acid, as well as the natural products, in a pro-drug concept.

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