Chemistry and Biology of Natural Products

This thesis is divided in four independent parts related to four different research projects. Each chapter describes one of the multiple aspects covered by organic chemistry, such as the generation of functional interfaces, understanding of biological processes at the molecular level or synthesis of natural products and derivatives as potential new therapeutic agents. These four chapters include an introduction and a description of the state of research in the domain. The experimental procedures as well as spectroscopic data are grouped in a special section at the end of the thesis. The first chapter is related to the problem of biofouling, which is the non-specific adsorption of macromolecules and bacteria and higher organisms to surfaces. It is considered a fundamental problem in many domains, ranging from human medicine to marine technology. Inspired by the binding properties of the anachelin H chromophore to metal oxides, we designed and evaluated PEG-conjugates bearing the native anchoring moiety or simplified analogs in order to generate antifouling surfaces. We also attached the antibiotic vancomycin to the PEG chain, creating a natural product hybrid that displayed antibacterial properties when tested against Bacillus subtilis ATCC 6633. The activity was retained even after repeated exposure to the bacteria. Natural products represent a major source of new drugs, especially in the field of anti-infective and anticancer agents. Different modes of action are known for natural products having cytotoxic activity, such as tubulin stabilization, DNA-cleavage or cell-wall disruption. The second chapter presents the study of the anticancer antibiotic anguinomycin, which is belonging to the leptomycin family and was reported to selectively target tumor cells. The role of its polyketide side-chain has been evaluated. Simplified compounds, which merge for example the natural lactone warhead and a terpene, have been tested for inhibition of CRM/-mediated nuclear export. Moreover, one mode of action of another natural styryl lactone, goniothalamin, has been elucidated by comparison of its potency with regard to modified analogs. This study should enable the design of new analogs displaying improved potency and selectivity and overcoming the reported toxicity of the native leptomycin. In the third part we describe synthetic studies towards the total synthesis of sporolide A and B. These complex natural products were isolated from the marine actinomycete Salinispora tropica in 2005. Their unusual architecture is striking, and contains 22 out of the 24 carbons that are either sp2 hybridized or oxygenated, 7 rings and 10 stereogenic centers rendering them very challenging targets for total synthesis. From a biological point of view, these compounds did not show interesting activity, probably because their potency resides in an enediyne precursor. As a consequence, we designed a putative biomimetic approach that would allow to accesfs the enediyne precursor. The synthetic studies towards the chlorinated cyclopenta[a]indene ring feature a Morita-Baylis-Hillman reaction, a Sharpless asymmetric dihydroxylation, enediyne formation via Wittig reaction and cerium mediated acetylide addition. The quinone acid fragment was obtained in 7 steps. The enantioselective transfer reduction was achieved using Ipc2BCl and the absolute configuration of the product was secured by X-ray analysis of its cinchonine salt. The fourth chapter describes the synthetic efforts towards the total synthesis ophiodilactone A and B, two tetrameric phenylpropanoids natural products isolated from the starfish (ophiuroid) Ophiocoma scolopendrina in 2009. They exhibit cytotoxicity against murine leukemia cells and could represent a new family of potential anticancer agents. Their syntheses are based on a two-directional approach followed by desymmetrization.