Total synthesis of bacterial and fungal lipidic natural products and their functional analysis as signaling molecules

Lipids and lipidic natural products occupy a pivotal role in the lifestyle of all organisms. To study their functions, access to synthetic standards and chemical tools is urgently needed. This thesis describes the total synthesis of three distinct lipidic natural products and the development of chemical probes for the deconvolution of their intriguing biological roles. In the first part, bacterial sulfonospingolipid, IOR-1A, was synthesized with a newly developed and modular total synthesis entailing a late-stage diversification step via decarboxylative cross-coupling, which allowed the preparation of IOR-1A-derived chemical probes. These probes were used in fluorescence microscopy and proteomics experiments to study the multicellular rosette-forming inhibitory activity of IOR-1A on the closest living single-celled relative to humans, the choanoflagellate Salpingoeca rosetta. The second part of the thesis elaborates on the first total synthesis of the fungal natural product sphingofungin C, a sphingolipid biosynthesis inhibitor. The highly modular approach entailed a decarboxylative amino acid synthesis enabling access to sphingofungin A, B, D, and four unnatural sphingofungin derivatives while being the shortest synthetic route reported towards this natural product family. Evaluation of the biological properties of the afforded sphingofungins suggested that this lipidic compound class could serve as a starting point for the development of new anti-protozoan therapies. The final part of this thesis discusses the first total synthesis of barnesin A, a newly discovered bacterial natural product. The novel synthetic approach allowed the elucidation of the correct stereochemistry of this lipodipeptide. Furthermore, the synthetically afforded quantities enabled the evaluation of barnesin A’s inhibitory properties against a selection of proteases ultimately leading to the discovery that this intriguing natural product is a selective cysteine protease inhibitor

Targeting antibiotic resistance

Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even lastresort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens

Antibiotikaresistenzen gezielt überwinden

Neue Strategien zur Bekämpfung von Antibiotikaresistenzen zu finden, ist eine der grössten globalen Herausforderungen für die Gesundheitssysteme. In den letzten Jahrzehnten gab es eine drastische Zunahme an humanpathogenen Bakterien, die resistent gegen Antibiotika sind. Immer mehr Infektionen, die durch resistente Mikroorganismen verursacht werden, lassen sich nicht mehr mit konventionellen Behandlungen kurieren, und selbst Reserveantibiotika verlieren ihre Wirkung. Zusätzlich sind die Entwicklungsströme an neuen Antibiotika aus der pharmazeutischen Industrie in den letzten Jahrzehnten versiegt. Die Weltgesundheitsorganisation hat mit ihrem Aufruf „Combat drug resistance: no action today means no cure tomorrow“ eine Zunahme der Forschungsaktivitäten auf diesem Gebiet stimuliert, und mehrere neue,vielversprechende Strategien zur Wiederherstellung antibiotischer Behandlungsoptionen konnten seitdem entwickelt werden

Total Synthesis and Functional Evaluation of IORs, Sulfonolipid‐based Inhibitors of Cell Differentiation in Salpingoeca rosetta

The choanoflagellate Salpingoeca rosetta is an important model system to study the evolution of multicellularity. In this study we developed a new, modular, and scalable synthesis of sulfonolipid IOR‐1A (six steps, 27 % overall yield), which acts as bacterial inhibitor of rosette formation in S. rosetta . The synthesis features a decarboxylative cross‐coupling reaction of a sulfonic acid‐containing tartaric acid derivative with alkyl zinc reagents. Synthesis of 15 modified IOR‐1A derivatives, including fluorescent and photoaffinity‐based probes, allowed quantification of IOR‐1A, localization studies within S. rosetta cells, and evaluation of structure‐activity relations. In a proof of concept study, an inhibitory bifunctional probe was employed in proteomic profiling studies, which allowed to deduce binding partners in bacteria and S. rosetta . These results showcase the power of synthetic chemistry to decipher the biochemical basis of cell differentiation processes within S. rosetta

Antiprotozoische Struktur‐Aktivitäts‐Beziehungen von synthetischen Leucinostatin‐Derivaten und Aufklärung ihres Wirkprinzips

Leucinostatin A ist eine der potentesten antiprotozoischen Verbindungen, die jemals beschrieben wurden, aber bisher war wenig über die Struktur-Aktivitäts-Beziehung (SAR) bekannt. Trypanosoma brucei wurde als Protozoen-Modellorganismus verwendet, um synthetisch modifizierte Derivate zu testen. Dabei wurden die vereinfachten, aber gleichermaßen aktiven Verbindungen 2 (ZHAWOC6025) und 4 (ZHAWOC6027) identifiziert. Anschließend wurden Modifikationen in allen Teilen des Moleküls durchgeführt, um ein besseres SAR-Verständnis zu erlangen. Die antiprotozoische SAR stimmte mit der SAR in Phospholipid-Liposomen überein, wobei die Membranintegrität, das Durchlässigkeitsverhalten und die Dynamik untersucht wurden. Die antiprotozoale Wirkung der natürlichen und synthetischen Leucinostatine liegt in der Destabilisierung der inneren Mitochondrienmembran, wie durch Ultrastrukturanalyse, Elektronenmikroskopie und Mitochondrienfärbung gezeigt wurde. Eine subletale Langzeitexposition von T. brucei (200 Passagen) und ein siRNA-Screening von 12′000 Mutanten zeigten keine Anzeichen einer Resistenzentwicklung gegenüber den synthetischen Derivaten

Creating of 2D Android game in Unity

U ovom radu izrađeno je programsko rješenje za Android igricu u Unity-ju te je uz Unity također korišten alat Microsoft Visual Studio. Rad se sastoji od opisa rada u pojedinim programima i samom objašnjenju koraka i programskoga koda. Na kraju rada objašnjeno je što to treba imati Android igrica da bi bila igriva na mobitelu te kratko o publiciranju

Creating of 2D Android game in Unity

U ovom radu izrađeno je programsko rješenje za Android igricu u Unity-ju te je uz Unity također korišten alat Microsoft Visual Studio. Rad se sastoji od opisa rada u pojedinim programima i samom objašnjenju koraka i programskoga koda. Na kraju rada objašnjeno je što to treba imati Android igrica da bi bila igriva na mobitelu te kratko o publiciranju

Creating of 2D Android game in Unity

U ovom radu izrađeno je programsko rješenje za Android igricu u Unity-ju te je uz Unity također korišten alat Microsoft Visual Studio. Rad se sastoji od opisa rada u pojedinim programima i samom objašnjenju koraka i programskoga koda. Na kraju rada objašnjeno je što to treba imati Android igrica da bi bila igriva na mobitelu te kratko o publiciranju

Software application development by using Microsoft Visual Studio

Cilj ovog diplomskog rada je izraditi Desktop Aplikaciju koristeći programsko okruženje Microsoft Visual Studio gdje su u teorijskom dijelu rada opisane osnovne značajke i mogućnosti softverskog okvira te u praktičnom dijelu izrađena proizvoljna aplikacija koja sadrži niz funkcionalnosti koristeći isti okvir. Ovim radom se demonstrirao postupak rada sa Microsoft Visual Studiom i njegovim mogućnostima kao što su jezik C#, WPF, LINQ, rad sa bazom podataka i drugo. Aplikacija koristi bazu podataka, a sama aplikacija je napravljena koristeći .NET Framework što je izvorna implementacija .NET-a koja podržava pokretanje Desktop aplikacija uz korištenje objektno orijentiranog programskog jezika C#. Grafičko sučelje je izrađeno koristeći grafički podsustav otvorenog koda WPF što je okvir za izradu Desktop klijentskih aplikacija. Ovaj okvir koristi Markup jezik XAML koji služi pružanju deklarativnog modela za programiranje aplikacija. Uz izradu aplikacije izrađena je i dokumentacija vezana uz aplikaciju

Software application development by using Microsoft Visual Studio

Cilj ovog diplomskog rada je izraditi Desktop Aplikaciju koristeći programsko okruženje Microsoft Visual Studio gdje su u teorijskom dijelu rada opisane osnovne značajke i mogućnosti softverskog okvira te u praktičnom dijelu izrađena proizvoljna aplikacija koja sadrži niz funkcionalnosti koristeći isti okvir. Ovim radom se demonstrirao postupak rada sa Microsoft Visual Studiom i njegovim mogućnostima kao što su jezik C#, WPF, LINQ, rad sa bazom podataka i drugo. Aplikacija koristi bazu podataka, a sama aplikacija je napravljena koristeći .NET Framework što je izvorna implementacija .NET-a koja podržava pokretanje Desktop aplikacija uz korištenje objektno orijentiranog programskog jezika C#. Grafičko sučelje je izrađeno koristeći grafički podsustav otvorenog koda WPF što je okvir za izradu Desktop klijentskih aplikacija. Ovaj okvir koristi Markup jezik XAML koji služi pružanju deklarativnog modela za programiranje aplikacija. Uz izradu aplikacije izrađena je i dokumentacija vezana uz aplikaciju