Synthesis of majucin-type sesquiterpenes and immobilization and visualization of quorum sensing signaling molecules

The science of chemical biology is the ability to answer biological questions by analyzing living systems at the chemical level. Two entirely different approaches to reach this goal are presented in this thesis. The work is divided in three experimental chapters and each one highlights the combination of modern synthetic chemistry with biological applications. Experimental data, spectroscopic analysis and appendices can be found at the end of this thesis.
Chapter 1 starts with a general introduction on important natural products that contributed to the progress of drug development in an historical perspective. The second part of this chapter presents the basic principle of combining multiple bioactive natural products to a single hybrid molecule and its potential application field.
Chapter 2 gives a broader introduction into the chemical communication used in the bacterial world. The communication pathways of Gram-positive and GramÐnegative bacteria are discussed with a special focus on the latter. The concept of quorum sensing and its importance in pathogenesis and biofilm formation are described in detail. The progress of synthetic signaling molecules that can modulate quorum sensing are discussed in chronological order.
The combination of molecular anchors to quorum sensing modulators is reported in Chapter 3. Inspired by the surface adherent properties of catechols, quorum sensing modulators were functionalized on metal oxide surfaces thereby maintaining their activity. The immobilized natural product hybrids were recognized by bacterial reporter strains as quorum sensing modulators. The mode of action was determined to be via slow release of the bioactive hybrid compounds.
The recognition pattern for quorum sensing receptors was further developed in Chapter 4 by the attachment of fluorescent dyes. First generation fluorescent labeling agents for quorum sensing (FLAQS) was successfully applied for the selective labeling of the CepR receptor used by Burkholderia cenocepacia. Further improvement of the fluorescent moiety allowed the first labeling of quorum sensing receptors in wild-type bacteria.
Second generation FLAQS bearing 3-oxo functionality in the acyl side chain were applied for the labeling of LasR, one of the quorum sensing receptors used by Pseudomonas aeruginosa.
A variety of natural products from Illicium species have been shown to possess exceptional neuritogenic properties. The synthesis of majucin-type sesquiterpenes and the preparation of 10-deoxy-jiadifenolide is the topic of Chapter 5. The synthetic key features include a cascade three-component reductive alkylation, a diastereoselective intramolecular Nozaki-Hiyama-Kishi coupling with a ketone, and an unprecedented cyanide addition to an aldehyde with subsequent lactonization under neutral conditions. The synthesis was accomplished in 25 linear steps with an overall yield of 3.7% for the first 24 steps.