D'Aniello, Filomena (2014) Characterization of new bioactive natural products from marine sources as pharmaceutical tools and lead compounds in drug discovery processes. [Tesi di dottorato]

Preview

Text d'aniello filomena.pdf Download (8MB) | Preview

Collection description

Natural products have historically been a rich source of “lead compounds” in drug discovery. The investigation of terrestrial plants and marine organisms aimed at searching new biologically active compounds is a central issue of this kind of studies, trough structure elucidation combined with biological tests. My research activity has been mainly devoted to the discovery and to the chemical and pharmacological investigation of new bioactive natural products as “lead compounds” in the area of antitumor, anti inflammatory and antimalarial activities. My research work, described in this PhD thesis, was organized in two different topics, i) isolation and structural characterization of bioactive secondary metabolites from marine invertebrates; ii) synthesis of quinones derivatives endowed with cytotoxic and antimalarial activities from natural lead compounds. The fulfilment of my research project required the use of different procedures of isolation and extraction. The chemical characterization of the isolated compounds has been performed through an extensive spectroscopic analysis (UV, IR, ECD, 1D and 2D NMR) together with mass spectrometry and computational methods. I have also used synthetic methods both for the chemical derivatization of the isolated molecules and for the preparation of analogues on the simplified model of natural molecules. During the course of research conducted during the PhD course and whose results are reported in the following thesis, I have dealt with the extraction and chemical analysis of different species of sea squirts (Aplidium conicum, Ciona edwarsii, Aplidium elegans, Phallusia fumigata and Sidnyum elegans) and of the sponge Axinella polypoides. This analysis led to the isolation of new molecules, which are structurally different, with interesting bioactivity. Among these, two new meroterpenes, conithiaquinones A and B, and three alkyl sulphates with cytotoxic properties. Three sulfated sterols, phallusiasterols A-C, one of them with agonist activity on the pregnane X receptor (PXR) in HepG2 cells. The phosphoeleganin, a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). An analysis of the metabolic content of the sponge Axinella polypoides has provided important chemo-taxonomic information about the organism, in addition, led to the isolation of a new betaine and a new cyclonucleoside. Within the study of compounds with antimalarial activity, in collaboration with the University of Rome La Sapienza and the Department of Public Health, Microbiology and Virology, University of Milan, I have performed the synthesis and evaluation of in vitro on strains of Plasmodium falciparum D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) of synthetic analogues of natural quinones, prepared on the pattern of two natural molecules previously isolated from an ascidian. The synthetic derivatives showed significant antimalarial activity and were also highlighted some structural requirements that are critical for the activity. Finally, during the period of research at the Institute of Materia Medica (SIMM ) in Shanghai, I started to study lipid-soluble extract of a fungal strain Penicillium sp, isolated from the Chinese mangrove Bruguiera gymnorrhiza. The analysis showed that the main component of the extract is a cytotoxic alkaloid, 2-(1-hydroxyethyl)-4 (3H) quinazolinone, which is currently subject to a broader drug screening.

Downloads

Actions (login required)

View Item