DEVELOPMENT OF BIOACTIVE NATURAL PRODUCTS:TOTAL SYNTHESIS AND STRUCTURE MODIFICATION TOWARD ANTIMICROBIAL AND ANTITUMOR AGENTS

Nowadays several challenges are threatening human’s quality of life. Global population is growing fast, and with that, the demand for food. Daily, 2.4 billion people struggle with food insecurity, facing either moderate or severe shortages that impact their lives and safety. [1] This date will probably keep worsening, as a 30% increase in population is expected to be reached by 2050. [2] In 2015, the United Nations established a plan of action made of 17 goals that must be fulfilled if we want to end poverty and hunger while improving health, education and equality by 2030. Agriculture has always been the primary source of food for humanity, and thus it is expected to play a pivotal role in this sustainable development program. However nowadays it is far from represent the excellent food system we are dreaming of. In this scenario a factor that could make a difference is working for decreasing food waste. As a matter of fact, huge crop losses are recorded in both pre-and post-harvest handling processes mainly because of the heavy impact of plant diseases. [3] Fungicides represent agriculture’s main weapon in this emergency, therefore improvements and innovations in this field are fundamental. A strategy to develop new environmentally friendly fungicides could be to switch from chemicals to biopesticides inspired by natural compounds (European Commission. Encouraging Innovation in Biopesticide Development. https://wayback.archive-it.org/12090/). The goal is to develop new highly efficient agrochemicals, with innovative modes of action, efficient to counteract development of resistant strains, and with milder impact on the soil as on the non-target organisms. Another burden impacting in the quality of life is the improper treatments used to counteract the highest fatality-related illnesses. First, there is the devastating threat of cancers, among the first cause of death worldwide. [4] Second, the challenges in counteracting the spreading of infections caused by multi-drug-resistant bacteria. [5] Even in this case chemicals are expected to play a central role and to be optimized to efficiently counteract the insurgence of resistant malignities. Moreover, diminishing the devastating drug related side-effects is urgent in the case of chemotherapy, while increasing the willingness and efficacy is fundamental in the development of antibiotics. The aim of my project was to explore the limitless source of bioactive molecules represent by nature, to develop new antimicrobial and antitumor compounds. NPs unique scaffolds, innovative mode of action, high bioactivity, and mild impact on the environment are just few of the intrinsic characteristics that make these scaffolds suitable to be considered in the development of leads compounds. As NPs are mostly secondary metabolites, produced by organism under well-defined conditions, their recovery from the natural matrix could be troublesome, low yielding and challenging for complex purification steps. [6] Therefore, the employment of natural compounds obtained directly from extracts is often impractical and tedious. In this context, the development of chemical and chemoenzymatic approaches to make natural molecules more accessible in high amount could open the possibility to improve the understanding and knowledge of NPs related biological activities. Moreover, structure modifications could be applied on identified natural leads compounds to try and expand the collection of compounds with nature-inspired analogues. These SAR studies could enable to find the best combination of chemical features, to obtain optimized new scaffolds with improved biological activity. In this project five classes of phytoalexins were considered: phenolamides, dehydrodiferulates, stilbenoids, iron-chelating hydroxamates, and thioamidates. These molecules are organisms’ secondary metabolites accumulated under biotic or abiotic stress conditions, which role in organisms’ self-defence mechanisms has already been reported in literature. Briefly, for NPs phenolamides and dehydrodiferulates a chemoenzymatic strategy was successfully applied to obtain high amounts of the natural molecules. Moreover, biological screening led to identification of some active compounds. As for dehydrodiferulates, structure modifications were applied resulting in the synthesis of some new scaffolds that, also in this case, turned out to be endowed with broad activity as both antimicrobials and cytotoxic compounds. The stilbenoids project was focused on the synthesis of multi-target antifungals, as strategy to enhance strobirulins effect on P. oryzae resistant strains. Finally, in this thesis the approach to the total synthesis of two NPs has been described. In the case of rhodotorulic acid our strategy was to obtain a short and scalable procedure, while for thioholgamide A its total synthesis has never been approached before This PhD project offered me the opportunity to collaborate with several research groups. The antifungal biological evaluation tests were performed in collaboration with the group of Prof. Andrea Kunova (Department of Food, Environmental and Nutritional Sciences, DeFENS, University of Milan), while the antibacterial tests in collaboration with the group of Prof. Piera Anna Martino (Department of Biomedical, Surgical, and Dental Sciences, DSBCO, One Health Unit, University of Milan) and Prof. Federico Baruzzi (Institute of Sciences of Food Production, CNR-ISPA, Bari). In the dehydrodiferulates project two international research groups were involved, the one of Prof. Jean-Paul Vincken (Laboratory of Food Chemistry, University of Wageningen, Netherlands) and that of Prof. Elke Richling (Department of Chemistry, Division of Food Chemistry and Toxicology, Technische Universität Kaiserslautern, Germany). Finally, I had the opportunity to take part on the total 71 synthesis of thioholgamide A project while hosted by Prof. Philipp Heretsch (Institut für Organische Chemie, University of Hannover, Germany) during my Erasmus stint. In the following chapters the identification and the design of new nature-derived antimicrobial and antitumoral agents will be described, starting from their synthesis to the investigation of their biological properties.