Pluda, Stefano (2013) Synthesis and reactivity of new hydroxamates of pterostilbene for biomedical applications. [Magistrali biennali]
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In this thesis work I explored the feasibility of using the hydroxamic functionality for the reversible protection of the hydroxy group of natural polyphenols: -OH → -O-N(R1)COR2. Many phenolic compounds exhibit, in vitro, interesting bioactivities with potential applications in human health care. However their bioavailability after ingestion is limited by the modifications of the phenolic functionality introduced by the enzymes of phase II metabolism. The prodrug strategy has thus been adopted to protect the sensitive sites and to increase the absorption of the active molecule. As model compound for the project I have used pterostilbene, a natural phenol with a vast potential for pharmaceutical applications. The thesis work has been performed in part in the laboratory of Dr. Sabine Amslinger of the Institute of Organic Chemistry of the University of Regensburg within the Erasmus program. Eleven new derivatives of pterostilbene have been synthesised, purified and characterized by mass spectrometry and 1H and 13C NMR spectroscopy. A study has been carried out of the reactivity of these derivatives in aqueous solution at pH values close to those of the body compartments involved in the absorption of orally administered drugs (stomach and first intestinal tract). The rate of hydrolysis and what products are obtained strongly depend on the nature of the R1 and R2 substituents. Some reaction intermediates have been identified and reaction mechanisms proposed, regarding also E, Z isomerism equilibria. Some of the compounds obtain show considerable stability both in strongly acidic (stomach-like) and neutral (intestine-like) solutions, and are therefore interesting candidates for more elaborated assays. Stability tests in blood and pharmacokinetic studies in vivo (rat) are currently under way in the laboratory of Dr. M. Zoratti of the CNR Institute of Neuroscience.
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