Nuevos compuestos citotóxicos de esponjas de Indonesia con naturaleza estructural diversauso de técnicas avanzadas en la determinación de su estereoquímica relativa y absoluta

Résumé

The dissertation presented below describes the examination of six sponges collected in Indonesia, and the identification of six new families of chemical compounds with cytotoxic activity. The most innovate part of this PhD thesis is the approach selected for the structural elucidation of the newly identified chemical entities, consisting in the combination of nuclear magnetic resonance techniques with density functional theory (DFT) based computational modelling. Chapter 1 introduces current perspectives regarding the use of natural products of marine origin for the development of pharmaceutical products, including ongoing industry developments in the different clinical markets. The state of the art of the different methods and techniques used for the identification of the chemical structure of the isolated compounds is also presented, focusing on the study of relative and absolute stereochemistry. These techniques will be used in the subsequent chapters for the resolution of the three-dimensional structure of the newly described chemical compounds. To facilitate the reading, the fractionation and isolation processes applied to all studied sponge extracts are presented in a schematic way. Chapter II describes the study of the sponge Hexadella sp. and the isolation of a cytotoxic bromotyrosine derivative named anomoian B. Chapter III presents the study of the Jaspis sp. and Bubaris sp. sponge association and the isolation of a new active brominated derivative named aplyzanzine B. The chapter also describes the mechanism of action of this new metabolite as well as of the previously described anomoian B. Chapter IV describes the study of the sponge Theonella sp. and the isolation of a new natural compound, lanesoic acid, with an unusual tetrahydropyrimidin skeleton combined with the zwitterionic nature of its chemical structure. Chaper V illustrates the isolation of new analogs of the enigmazoles family from the sponge belonging to the family Neopeltidae. Different chemical derivatization procedures were required for the stereochemical resolution of these compounds with cytotoxic activity. Chapter VI describes the isolation of halioxepines A, B and C from the sponge Haliclona (Reniera) sp., and the computational modelling required for relating the different stero-clusters present in the three molecules. Finally, Chapter VII illustrates the isolation of a new cyclic peptide, gunungamide A, and the applicability of configurational analysis based on coupling constants in combination with the advanced Marfey's method, to facilitate the relative and absolute stereochemical resolution of the amino acids present in the peptidic skeleton of this compound. This new combined methodological approach was also applied to the compound stellatolide A.