From bioactive natural products to drug-like small molecules

Abstract

Natural products have historically been the most productive source of leads for the development of drugs. Thanks to the chemical methodologies of natural products, a vast array of bioactive secondary metabolites from terrestrial and marine sources has been discovered. Many of these natural products became current drug candidates. Therefore, the research of new biologically active compounds through structure elucidation and biological tests is the central issue of these studies. My research is placed in this field and it has been mainly devoted to the discovery and to the chemical and pharmacological investigation of new bioactive natural products as “lead compounds” in the antitumor and antimalarial activities area. My 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 thiazinoquinones derivatives endowed with cytotoxic and antiplasmodial activities from marine natural metabolites. The achievement of my research project required isolation and extraction procedures. 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, computational and electrochemistry 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 my PhD research, whose results are reported in the following thesis, I have been dealing with the extraction and the chemical re-investigation of a new collection of the Mediterranean ascidian Phallusia fumigata. This analysis led to the isolation of one sulfated sterol, phallusiasterol C, which is a possible modulator of the PXR nuclear receptor. Morover, I have been strongly involved in completing the stereochemistry assignment of phosphoeleganin, a complex acyclic marine natural product, isolated previously from the Mediterranean ascidian Sidnyum elegans. In addition, the electrochemical response of four natural cytotoxic thiazinoquinones, beforehand isolated and characterized from Aplidium species, has been investigated, in order to clarify the mechanism of action which is the basis of their cytotoxicity. The research for new antiplasmodial hits is another main topic of my PhD activity discussed in this thesis. Previously, having identified the thiazinoquinone nucleus as new active chemiotype against P. falciparum, my research started from the development of two new series of methoxy and amide derivatives inspired by two marine metabolites isolated from the Mediterranean ascidian Aplidium conicum. Recently, in order to refine this pharmacophore model and improve the pharmacokinetic and pharmacodynamic properties, I have performed a rational design and synthesis of new modified analogues with simplified side chains and different substituents. In collaboration with the Department of Biomedical, Surgical and Dental sciences (University of Milan), the synthetic analogues of natural quinones have been tested for their in vitro antiplasmodial activity against both chloroquine (CQ)-sensitive (D10) and -resistant (W2) strains of P. falciparum, although some of them were strongly cytotoxic. Some of the synthetic derivatives showed significant antiplasmodial activity together with some important structural requirements. Additionally, in order to rationalize the structure-activity relationships (SARs), an integrated approach based on computational and electrochemistry studies was performed. These studies were carried out by a further collaborating external research group. The above results clearly evidence that quinone natural products represent an excellent source of novel “drug-like” small molecules for drug discovery in antimalarial research.