Vollsynthetische Darstellung von Jacaranon-Glukosiden

2011 wurde von Gachet et al. bei ethnopharmazeutischen Untersuchungen in Südamerika eine neue Leitsubstanz mit vielversprechenden, antiplasmoidalen Eigenschaften entdeckt. Diese aus dem Tropengehölz Jacaranda glabra isolierten Jacaglabroside zeichneten sich durch eine komplexe Glycosid-Struktur mit wechselnden Aglyca-Resten an den 5 Hydroxidfunktionen des zentralen Glucosebausteins aus. Frühere Untersuchungen auf diesem Gebiet, vor allem von Meier [2014] deuten darauf hin, dass es sich bei den Dienon- Strukturen der Aglyca um die wirkungsbestimmenden Grundstrukturen handelt. Ziel der hier vorlegenden Arbeit war die Darstellung von Jacaranon-Glykosiden. Daraus sollten Hinweise auf die pharmakologisch aktiven Strukturelemente erhalten werden. Dazu wurden selektiv geschützte Glucosegrundkörper hergestellt. Bei den verwendeten Schutzgruppen handelte es sich um Allyl-, Benzyl- sowie Benzylidengruppen. Anschließend wurden die Zucker mit dem wirkungsbestimmenden Aglycon, einem Tyrosolderivat, verestert. Die Oxidation zu den pharmakologisch aktiven Dienonen erfolgte im letzten Schritt mit PIDA. Zur Evaluierung ihrer antiplasmoidalen Eigenschaften und ihrer Zytotoxizität wurden die neu synthetisierten Leitsubstanzen an das Swiss Tropical and Public Health Institute in Basel übermittelt. Trotz der starken strukturellen Homologie zu den natürlich vorkommenden Jacaglabrosiden scheinen die getesteten Verbindungen jedoch keine biologische Aktivität aufzuweisen.During ethnopharmaceutical surveys conducted by Gachet et al. in 2011 a promising new agent with antiplasmoidal properties was found in South America. These so called Jacaglabrosides where isolated from the tropical plant Jacaranda glabra and are characericed by their complex glucosidic structure, with several different aglycons annealed to a main glucose body. A fully synthetic approach for producing these substances under laboratory conditions was underway since 2011, with remarkable advances in the field by Meier [2014]. The main goal of this thesis was to find a fully synthetic way of producing the natural glucoside as well as the synthesis of another Jacaglabroside-derivative to narrow down the pharmacologically active structure elements. Allyl- , benzyl- and benzylidene protecting groups where introduced and selectively cleaved to yield the desired protected glucose-derivative, which was later on annealed to the precursor of the pharmacologically active aglycon by esterification. The aglycon-precursor was then oxidized to its active form using PIDA. The biological properties of these new substances were evaluated at the Swiss Tropical and Public Health Institute in Basel (Switzerland). Although the newly synthesised substances show a strong resemblance to their natural counterparts they have shown no signs of biological activity.Kalt Marc-ManuelAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. und engl. SpracheGraz, Univ., Dipl.-Arb., 2014(VLID)447726

Synthesis of Jacaranone-Derived Nitrogenous Cyclohexadienones and Their Antiproliferative and Antiprotozoal Activities

The cytotoxic and antiprotozoal activities of the phytoquinoide, jacaranone, and related compounds have been an ongoing topic in recent drug discovery. Starting from the natural product-derived cyclohexadienone scaffold, a series of nitrogen-containing derivatives were synthesized and subsequently evaluated for their antiproliferative and antiprotozoal activity. Anticancer potency was analyzed using different types of cancer cell lines: MDA-MB-231 breast cancer, CCRF-CEM leukemia, HCT-116 colon cancer, U251 glioblastoma, and, in addition, non-tumorigenic MRC-5 lung fibroblasts. Antiproliferative activities at micromolar concentrations could be shown. Antiprotozoal activity was assessed against Plasmodium falciparum NF54 and Trypanosoma brucei rhodesiense STIB900. For all compounds, selectivity indices (SI) were calculated based on assessed cytotoxicity towards L6 cells. In addition, the structure-activity-relationships and physicochemical parameters of these compounds are discussed