Sinisi, Annamaria (2015) Isolation and structural elucidation of bioactive secondary metabolites from marine and terrestrial organisms. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Isolation and structural elucidation of bioactive secondary metabolites from marine and terrestrial organisms
Creators:
CreatorsEmail
Sinisi, Annamariaannamaria.sinisi@unina.it
Date: 29 March 2015
Number of Pages: 158
Institution: Università degli Studi di Napoli Federico II
Department: Farmacia
Scuola di dottorato: Scienze farmaceutiche
Dottorato: Scienza del farmaco
Ciclo di dottorato: 27
Coordinatore del Corso di dottorato:
nomeemail
D'Auria, Maria Valeriamadauria@unina.it
Tutor:
nomeemail
Taglialatela-Scafati, OrazioUNSPECIFIED
Date: 29 March 2015
Number of Pages: 158
Uncontrolled Keywords: marine invertebrates; plants; natural substances
Settori scientifico-disciplinari del MIUR: Area 03 - Scienze chimiche > CHIM/06 - Chimica organica
Date Deposited: 10 Apr 2015 11:31
Last Modified: 25 Sep 2015 11:07
URI: http://www.fedoa.unina.it/id/eprint/10190
DOI: 10.6092/UNINA/FEDOA/10190

Abstract

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, through structure elucidation combined with biological evaluation. My research work, described in this PhD thesis, falls within this research field and was addressed at three different topics: - i) isolation and structural elucidation of cytotoxic macrolides and depsipeptides and sterols active on PXR receptors from sponge Theonella swinhoei; ii) isolation and structural elucidation of metabolites modulating kinase activity from sponge Iotrochota purpurea; iii) isolation and analysis of correlation between reactivity and bioactivity for antimalarial and antinflammatory metabolites from the African plant Vernonia amygdalina. The structure elucidation of new molecules was performed using advanced spectroscopic techniques (2D-NMR and MS) and advanced methods of stereochemical determination (Murata's method and Marfey's method). The chemical investigation of spongal metabolites carried out during my PhD was financed by the European project "Bluegenics". Several structurally interesting bioactive molecules have been isolated from Theonella sp., namely swinholides (cyclic 44-member macrolides) and theonellapeptolides (cyclic tridecadepsipeptides with a large amount of non-ribosomial amino acids), both featuring in vitro antiproliferative activity and providing important information regarding structure-activity relationship. The class of 4-methylensterols, typical of Theonella sponges, showed activity on nuclear receptor PXR, shedding light on structure-activity relationships useful for synthesis of lead compunds to be used for therapy of metabolic diseases. Regarding the second topic, the isolation of haloindole derivatives, by bioguided approach, allowed their evaluation for antikinase activity, which could have an important impact on the manipulation of cell proliferation, diabetes, and neurodegenerative disorders. Finally, a bioguided analysis of Vernonia amygdalina, a plant from Africa used as foodstuff and as drugs in the folk medicine, allowed the characterization of plant extracts for stage specific effects on gametocytes and sporogonic stages of Plasmodium and identification of compounds responsible for antimalarial activity. In particular, leaves of V. amygdalina contain sesquiterpenes lactones vernolide and vernodalol featuring this kind of activity; thus, they have a potential for drug discovery and for the development of standardized V. amygdalina based phytomedicines. The second aim of the investigation on V. amygdalina was the isolation and structural elucidation of a series of sesquiterpenes compounds with Michael related bioactivity, capable of shedding light on the molecular mechanisms underlying the anti-inflammatory and anticancer activities detected for the extract. On these series, cysteamine assay proved to be a tool to build a sort of Michael-oma profile of this class of metabolites, identifying the most reactive site in polyfunctional compounds and ranking them in terms of reactivity. Considering the correlation between thia-Michael acceptor reactivity and modulation of important biological target, sesquiterpene lactones were evaluated on transcription factors NF-κB, STAT3 and Nrf2 involved in cancer initiation and progression, concluding that vernolide is the major anti-inflammatory constituent of extracts and elucidating the anticancer activity reported.

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