Addressing fundamental questions in chemical biology through biochemical investigations of natural products

This thesis is separated in three main parts including a general introduction, three chapters based on research projects and the last chapters with the experimental procedures and analytical data. The focus of this work is based on the isolation of natural products and their application in chemistry and biology.
Chapter 1: The first chapter consists in a general introduction about natural products, where their importance in drug discovery and in the interaction between living organisms is highlighted. Several examples of natural products from different origins are described.
Chapter 2: The study of a system living in obligatory symbiosis is addressed in this chapter. Psychotria kirkii is a plant having the particularity to be in symbiosis with a bacterial strain named Candidatus Burkholderia kirkii and the presence of this microorganism was found to be essential for the plant’s survival. Interestingly, the bacterial genomic sequencing and analysis revealed the presence of a putative C7N aminocyclitol. This project led to the isolation, total synthesis and biological evaluation of kirkamide, a new C7N aminocyclitol from Candidatus Burkholderia kirkii. In the course of the chemical composition analysis of Psychotria kirkii, another new natural product (streptol glucoside) was isolated and its structure was elucidated. The last part of this chapter focuses on detection and quantification methods for the analysis of these natural products.
Chapter 3: After completing a genome-driven bioassay-guided fractionation, a natural product possessing an unusual N-nitrosohydroxylamine functional group was isolated. The formation of the N-N bond in biological system has yet to be elucidated. Chapter 3 addresses the question regarding the biosynthetic analysis of the N-nitrosohydroxylamine compound. Furthermore, the mechanism of the N-N bond formation was investigated in detail using model compounds.
Chapter 4: The potential of secondary metabolites has been recognized for the discovery of biological active compounds. The strength of natural products resides in the diversity and complexity of their chemical structures. In this chapter the isolation, structure elucidation and biological evaluation of new natural products from cyanobacteria are described. Three new cyanobactins were isolated from the cyanobacteria Microcystis aeruginosa EAWAG 251. The stereoassignement of these natural products, named balgacyclamides A–C, is presented with their biological activity investigations against the parasite Plasmodium falciparum. The last part of the chapter describes a bioassay-guided fractionation leading to the discovery of two new glycolipopeptides from cyanobacteria. The efforts achieved towards the structure elucidation using HRMS tandem mass spectrometry, NMR and amino acid analysis are presented.