Caso, Alessia (2018) Novel bioactive metabolites from marine sources: isolation, structural elucidation and synthetic studies. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Novel bioactive metabolites from marine sources: isolation, structural elucidation and synthetic studies.
Creators:
CreatorsEmail
Caso, Alessiaalessia.caso@unina.it
Date: 7 June 2018
Number of Pages: 204
Institution: Università degli Studi di Napoli Federico II
Department: dep05
Dottorato: phd071
Ciclo di dottorato: 30
Coordinatore del Corso di dottorato:
nomeemail
D'Auria, Maria Valeriamadauria@unina.it
Tutor:
nomeemail
Costantino, ValeriaUNSPECIFIED
Date: 7 June 2018
Number of Pages: 204
Uncontrolled Keywords: marine natural products, chemical synthesis, stereoselective total synthesis, structure elucidation, antitumor activity, smenospongia aurea, smenospongia conulosa, geodia cydonium
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/06 - Chimica organica
Date Deposited: 13 Jun 2018 14:18
Last Modified: 06 Mar 2019 09:22
URI: http://www.fedoa.unina.it/id/eprint/12293

Abstract

Among marine organism, Porifera have proven to be a rich source of new metabolites. Sponge are sessile organisms, therefore lacking any physical defence against predators. To make up to this lack, they produce species-specific molecules, known as secondary metabolites, which may play a key role in interspecific competition, defense against predators and reproduction processes. Secondary metabolites of marine origins are interesting molecules, often characterised by complex and unusual structures, which have shown to have a broad spectrum of pharmacological activities, such as anti-inflammatory, antiviral, antibiotic and anticancer. These compounds are hence considered promising lead compounds in drug discovery. Recently, many marine natural products have been approved, and others are in clinical trials. Due to the small amount isolated from the marine source, the evaluation of the biological activity of these compounds is often limited. Many alternatives have been considered to solve this issue. The total or semi-synthesis of these compound represents a valide alternative to provide greater amounts of the metabolites of interest, allowing to gain a better insight in their biological activity. Currently, the number of synthetic or semi-synthetic drugs is indeed strongly increasing. This research field forms the backdrop to my PhD work, aimed to the identification and structural elucidation of new bioactive marine natural products and to the synthesis of analogues with improved biological activities. The main topic of my reseach activity was the total synthesis of hybrid peptide/polyketide compounds of marine origins. Simultaneously, I was involved in the analysis of the chemical content of the Caribbean sponge Smenospongia conulosa and the Mediterranean sponge Geodia cydonium. The analysis of the lipofilic extract of the Caribbean sponge S. aurea led to the isolation, in 2013, of two hybrid peptide/polyketide compounds: smenamide A and B. Although both compounds possess a cytotoxic activity at nanomolar levels, smenamide A resulted more active blocking the cell proliferation through a pro-aapoptotic mechanism. Therefore the total synthesis of smenamide A and its analogues was undertaken in order to provide greater amount of the compounds needed to confirm the structure of the compound, determine the absolute configuration at C-16, that remained undetermined until the end of the synthetic project, and to further investigate the cytotoxic activity. The total synthesis resulted in the preparation of 16-epi- and ent-smenamide A, two synthetic analogues of smenamide A. In order to investigate the role of the structural determining-features of smenamides family, eight shorter-chain analogues of the synthetic 16-epi-smenamide A have been designed and prepared. The evaluation of the antiproliferative activity of 16-epi-smenamide A, together with its analogues, is now in progress. On the other hand, the analysis of the organic extracts of the Caribbean sponge Smenospongia conulosa and the Mediterranean sponge Geodia cydonium led to the identification of two new hybrid peptide/polyketide compounds, conulothiazole A and B, and an active fraction, respectively. The evaluation of the biological activity of conulothiazoles could not be carried out because of the low amount isolated from the marine source. As for G. cydonium active fraction, it showed an antiproliferative activity on three humar cancer breast cell lines (MCF-7, MDA-MB-231 and MDA-MB-468). The use of LC-HRMS, LC-HRMS/MS coupled with a bioinformatic techniques, e.g. Molecular Networking, as a novel dereplication strategy allowed to identify most of the metabolites contained in this fraction. In addition, the evaluation of the metabolomic profiling and the cytokine levels of the three cancer cell lines after treatment with the active fraction showed that the latter participates in the modulation of several metabolites in pro- or anti-tumor processes. Further studies are necessary in order to understand the mechanism of action of each compound contained in this fraction, as well as the evaluation of the possible synergistic effect of a pool of compounds.

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