Isolation and Structure Elucidation of Bioactive Secondary Metabolites from Marine and Terrestrial Organisms.
Chianese, Giuseppina (2011) Isolation and Structure Elucidation of Bioactive Secondary Metabolites from Marine and Terrestrial Organisms. [Tesi di dottorato] (Inedito)
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Natural products have historically been a rich source of “lead compounds” in drug discovery. The investigation of terrestrial plants and marine organisms aimed at searching new biologically active compounds is a central issue of this kind of studies, trough structure elucidation combined with biological tests. My research work, described in this PhD thesis, is included in this research topic and was addressed at three different topics: - cannabinoids from Cannabis sativa and from the Indonesian sponge Dasychalina sp.; - isolation and synthesis of antimalarial compounds; - metabolites isolated from plants belonging to the Euphorbiaceae family (Jatropha curcas, Euphorbia macroclada and Euphorbia bungei). A phytochemical investigation of the fibre cultivar of Cannabis sativa derived from the historical Carmagnola variety led to isolation of the novel spiranic stilbenoid isocannabispiradienone and the biphenyl-type cannabinoid cannabioxepane (CBX), a tetracyclic compound characterized by an unprecedented C-5/C-8’ oxygen bridge and devoid of cannabinoid activity. In the same area, from the polar organic extract of the Indonesian sponge Dasychalina sp., I have isolated haplosamate A, a unique C28 sterol containing a sulfate group at C-3 and a methyl phosphate at C-15, along with its new desulfo analogue. Both compounds, as well as their semi-synthetic analogues, have been evaluated for interaction with CB1 and CB2 receptors through a binding test. Desulfohaplosamate showed a selective affinity for CB2 receptors in the low μM range. Haplosamate derivatives represent the first CB receptor ligands belonging to the class of steroids. The search for antimalarial lead compounds is another main topics of my Ph.D. activity discussed in this thesis. On the bases of the previously developed pharmacophore of plakortin antimalarials, in this thesis I report a synthesis of a new series of simple endoperoxides, characterized by a 3-methoxy-1,2-dioxane scaffold. In particular, I have contributed to the design, the synthesis, the biological evaluation of a novel series of compounds obtained by means of an efficient one-pot three-component Mn(III)-mediated synthesis which utilizes cheap starting materials. The obtained molecules are 3,6,6-trisubstituted 3-methoxy-1,2-dioxanes with simple alkyl chains and bearing an ester group at position 4, which were tested against Pf. As part of the ongoing research aimed at finding new antimalarial leads from natural sources, I have carried out a detailed phytochemical investigation of the fruit of an African sample of Azadirachta indica, collected in Burkina Faso. Eight known and two new triterpenoid derivatives, named neemfruitins A and B, have been isolated from the fruits of neem, Azadirachta indica A. Juss., a traditional antimalarial plant used by Asian and African populations. In vitro antiplasmodial tests carried out with the isolated metabolites evidenced a significant activity of the known gedunin and azadirone and the new neemfruitin A, and provided useful information about the structure-antimalarial activity relationships in the limonoid class. Finally, the chemical investigation of Euforbiaceae plants carried out during my Ph.D., and described in this thesis, led to isolation of many diterpenoids. From the root barks of Jatropha curcas I isolated spirocurcasone, a diterpenoid possessing the unprecedented “spirorhamnofolane” skeleton, along with 11 known and two other new diterpenoids. The absolute configuration of spirocurcasone was established using quantum mechanical calculation of the electronic circular dichroic (ECD) spectrum. Some of the isolated diterpenoids showed a potent activity against L5178Y, a mouse lymphoma cell line. The phytochemical investigation of Euphorbia macroclada Boiss. and Euphorbia bungei, led to isolation of many new diterpenoids belonging to the jatrophane and pre-myrsinane classes. The main interest in these compounds is related to their biological activity as glycoprotein-P inhibitors and so modulators of multidrug resistance in cancer chemotherapy. The structures of all new compounds were elucidated using modern spectroscopic methods including 2D NMR and HRMS.
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