Festa, Carmen (2010) Secondary metabolites from natural sources: chemical and pharmacological characterization. [Tesi di dottorato] (Inedito)

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Abstract

Natural products have long been a source of bioactive metabolites utilized for the treatment of human disease. In spite the impressive progress of new competing methodologies, as for example, combinatorial chemistry and high-throughput screening or genetic engineering, natural products remain a valuable source of bioactive compounds with therapeutic potential. In recent years, the marine environment has been seen as a vast resource for the discovery of structurally unique bioactive secondary metabolites, some belonging to totally novel chemical classes. In particular the Porifera have developed an arsenal of new compounds. Part of my research work is collocated within this area and concerns the investigation of the natural products deriving from marine sponges. In the frame of the project C.R.I.S.P. (Coral Reef Initiative of South Pacific), directed to the chemical investigation and valorisation of the marine invertebrates of South Pacific, particular attention was paid to two sponges: Theonella swinhoei and Coscinoderma mathewsi. From these sponges, several structurally interesting bioactive molecules have been isolated with promising biological activities. Worthy of note are perthamides, a family of cyclic octapeptides, encompassing majority of non-proteogenic amino acids, and solomonamides which represent a new class of cyclic peptides, featuring a potent in vivo anti-inflammatory activity. Solomonsterols have been demonstrated the first examples of sulfated sterols with a truncated side chain from a marine source endowed with a PXR agonistic activity. The structure elucidation of these new molecules was performed using the most modern sophisticated spectroscopic techniques (2D-NMR and MS). The main interest in these compounds is related to their strong biological activity, that had led to pharmacological investigations on biomolecular target, the mechanism of action and the pharmacophore useful in the identification of new leads for developing a new generation of drugs. The detailed pharmacological investigation has in some cases required the access to adeguate amount of natural products or of semisynthetic derivatives through chemical synthesis, an issue addressed in a research parallel to the present work. The stereochemical novelty and complexity of some amino acid units of cyclopeptides have required a tailored integrated approach which combined NMR methods, stereoselective synthesis and LC/MS The second part of my research has been employed and addressed on the analysis of plants of Mediterranean area and used as foodstuff and as drugs in the folk medicine, to isolate the active principles with biological activity and nutraceutical property. In this respect, my research objectives have been to identify the chemical constituents from three plants Cucumis melo, Borrago officialis and Ruscus aculeatus. It is clear that Nature continues to be a major source not only of potential chemotherapeutic agents but also of lead compounds that have provided the basis and inspiration for the semisynthesis or total synthesis of effective new drugs; natural product chemistry has enriched both organic chemistry and medicine in a myriad of different ways.

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