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Azzolini, Michele (2015) Pharmacology of natural polyphenols: prodrugs and biochemistry of Resveratrol and Pterostilbene. [Ph.D. thesis]

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Abstract (english)

This thesis deals with aspects of the pharmacology of two polyphenols: Resveratrol and Pterostilbene.
These plant-made molecules are the object of intensive research due to their biological and biomedical activities, of interest in the context of various pathologies related to age, inflammation, neurodegeneration, cancer, obesity and diabetes. However, the mechanisms underlying the activity of Resveratrol, and in particular of Pterostilbene, are not completely known. Moreover, the presence of free hydroxyl group(s) (the common feature of polyphenols) renders both molecules good substrates for enzymes of phase II metabolism, whose activity strongly limits the bioavailability and the pharmacological exploitation of polyphenols.
During my graduate studies I have worked on both these themes. I will describe first what has been done to increase the bioavailability of both molecules. Second, I will summarize my ongoing investigation of the molecular mechanisms accounting for the activity of Pterostilbene and Resveratrol.
The strategy adopted by my research group to improve the efficacy of these polyphenols, viewed more as pharmaceuticals than as nutrients, involves the use of prodrugs. Prodrugs are essentially protected versions of a given molecule. Resveratrol in particular presents three main sites that ought to be protected from phase II enzymes, the hydroxyl groups. Through chemical derivatization (performed by the group of prof. Cristina Paradisi) the hydroxyl groups were reversibly protected with pro-moieties. The choice of linker group and of the pro-moiety is of fundamental importance to construct a useful prodrug. We intend prodrugs as therapeutic molecules designed for oral administration. This route of administration demands a suitable stability in gastric and intestinal environments, and a moderate instability in other physiological matrices (e.g. blood, tissues, extracellular fluids) so as to regenerate the active polyphenol once in the latter. During my PhD project we have optimized the two key components of the prodrug, the bond and the substituent group, working with Resveratrol, and we have then applied the results to Pterostilbene.
I started my project working on acetal derivatives of Resveratrol. We produced and tested a series of derivatives bearing short ethyleneglycol oligomers (OEG) linked to the phenolic oxygens via acetal/formal/ketal bonds. Through ex vivo and in vivo tests we have identified the acetal derivative Resv-O-CH(CH3)-OR, with R = tetrameric OEG, as the most promising prodrug of this series (chapter 1, “Acetal derivatives as prodrugs of resveratrol”).
Complete deprotection to give Resveratrol was however rather slow. We thus decided to test new derivatives based on a different bond system, and different substituent groups. Chapter 2, “New water-soluble carbamate ester derivatives of resveratrol”, presents the results obtained with Resveratrol derivatives bearing a PEG 350 or a sugar promoiety joined to the stilbenoid core through a N,N-di-substituted carbamate ester functionality. These molecules present the advantage of an increased water solubility, while maintaining to some degree the ability to permeate membranes. However, the high stability of these molecules was again problematic.
The stability vs. hydrolysis of the carbamate bond can be modulated varying the number and characteristics of the substituents on the Nitrogen atom; we tested therefore the N-mono-substitute carbamate group, which we expected to be more labile than its di-substitued analog. Chapters 3 and 4 (respectively “N-monosubstituted carbamate ester derivatives of resveratrol” and “Synthesis and evaluation of hydrophilic carbamate ester analogos of resveratrol”) present two series of derivatives of Resveratrol comprising amino acids, short ethyleneglycol oligomers (OEG) or sugar promoities linked to the scaffold via this group. The N-mono-substituted version of the carbamate bond shows high stability in acid, a suitable stability at near-neutral pH, and it undergoes hydrolysis with opportune kinetics in rat blood. The stability of these molecules depends in part on the substituent group on Nitrogen. However most of our derivatives hydrolyzed with a time course compatible with their use as prodrugs of Resveratrol (chapter 3).
Besides its rapid phase II metabolism, Resveratrol is also poorly soluble in water. Its administration is therefore usually as pills or with excipients. Water-soluble prodrugs would facilitate Resveratrol administration, especially if given chronically. In chapter 4 I present Resveratrol derivatives in which all three, two or one hydroxyl group(s) are incorporated into N-monosubstituted carbamate ester moieties; in these molecules the pro-moiety is a polyhydroxylated group (dihydroxypropyl or 6-deoxygalactose), and confers high water solubility. Galactosyl derivatives were substantially confined to the intestine, where they accumulated especially in the lower segments, undergoing the progressive loss of the protecting groups. Dihydroxypropyl derivatives instead were partly absorbed. Notably, the best results were achieved using mono-substituted derivatives.
I have then applied the knowledge and know-how gained working with Resveratrol to Pterostilbene, the 3,5-dimethylated analogue of Resveratrol. Since Pterostilbene is still poorly characterized from a pharmacological point of view we first of all performed a detailed analysis of the distribution of the molecule and its major metabolite in the organs of rat after its oral administration (chapter 5, “Pharmacokinetics and tissue distribution of pterostilbene in the rat”). The levels of Pterostilbene in the organs were much higher than those measured in blood. Nonetheless, its sulfate was the predominant specie in all tissues examined except the brain.
We tested a small library of pro-drugs of Pterostilbene bearing amino acids linked to the phenolic oxygen via the N-monosubstitute carbamate ester group. As expected, the rates of hydrolysis of these derivatives fell in a range suitable for their use as prodrugs. Absorption of Pterostilbene derivatives bearing apolar amino acids was greatly increased (chapter 6, “Boosting pterostilbene’s effects: a prodrug approach”). Apart from an intense and sustained absorption from the intestinal wall, a few precursors were notable for the levels of Pterostilbene they regenerated in blood. One of these compounds was selected as the most promising one and its distribution in rat organs was analyzed, following the same criteria adopted for Pterostilbene (described in chapter 5). The prodrug itself was the major specie measured in all organs examined, except the brain, while levels of the sulfate metabolite were decreased and those of regenerated Pterostilbene increased in most of the organs examined (in comparison with the administration of Pterostilbene itself). Prodrugs can thus be a useful tool to increase the bioavailability of some polyphenols.
In the second phase of my PhD project I conducted an investigation, still to be completed at this point, of the cellular processes set in motion by Pterostilbene and Resveratrol. For this purpose we adopted in vitro and in vivo approaches, presented here in two separate chapters, focused on the induction of autophagy and on the modulation of aged-impaired cognitive processes, respectively
Finally, during my doctoral training I have also been involved in other ongoing projects in my group. This involvement has led to my presence in the author list of three publications, which I include in this thesis as chapters 9, 10 and 11.

Abstract (italian)

Questa tesi riguarda aspetti della farmacologia di due polifenoli: il Resveratrolo e lo Pterostilbene.
Queste molecole di origine vegetale sono oggetto di intensa ricerca alla luce dei loro effetti biologici e biomedici, d’interesse per varie e distinte patologie legate all’età, infiammazione, cancro, obesità, neurodegenerazione e diabete. Tuttavia i meccanismi alla base dell’attività del Resveratrolo ed in particolare dello Pterostilbene non sono completamente noti. Inoltre, la presenza di gruppi idrossilici liberi (caratteristica tipica dei polifenoli) rende queste molecole un buon substrato per gli enzimi del metabolismo di fase II, la cui attività ne limita fortemente la biodisponibilità e lo sfruttamento farmacologico.
Nel corso del mio dottorato mi sono occupato di entrambi questi temi. Descriverò prima il lavoro fatto per aumentare la biodisponibilità delle molecole precedentemente menzionate. In secondo luogo riassumerò le indagini sui meccanismi molecolari che sottendono l’attività dello Pterostilbene e del Resveratrolo.
La strategia adottata dal mio gruppo per aumentare la biodisponibilità di questi polifenoli, considerati alla stregua di farmaci, si basa sull’uso di pro-farmaci. I pro-farmaci sono essenzialmente versioni protette di una determinata molecola. Il Resveratrolo in particolare presenta tre siti principali che dovrebbero essere protetti dagli enzimi del metabolismo di fase II, i gruppo idrossilici. Attraverso un processo di derivatizzazione chimica (svolto dal gruppo della prof.ssa Cristina Paradisi) i gruppi idrossilici sono stati protetti con dei gruppi sostituenti. La scelta della funzionalità chimica e dei sostituenti usati per la protezione è fondamentale per ottenere un pro-farmaco utile. Noi intendiamo i pro-farmaci come molecole terapeutiche adatte per la somministrazione orale. Questa via di somministrazione presume un’elevata stabilità negli ambienti gastrici ed intestinali, seguita da una moderata instabilità in altri ambiti fisiologici (sangue, tessuti, fluidi extracellulari) così da rigenerare il polifenolo naturale, attivo. Durante il mio progetto di dottorato abbiamo ottimizzato questi componenti dei pro-farmaci, il legame ed il gruppo sostituente, lavorando con il Resveratrolo, e poi abbiamo applicato i risultati ottenuti allo Pterostilbene.
Ho iniziato lavorando su derivati acetalici del Resveratrolo. Abbiamo prodotto e testato una serie di composti “decorati” con brevi oligomeri di glicole etilenico legati agli ossigeni fenolici con dei legami di tipo acetalico. Tramite esperimenti ex vivo ed in vivo abbiamo identificato la molecola con quattro unità di glicole etilenico ed il legame acetale propriamente detto (Resv-O-CH(CH3)-OR) come pro-farmaco più promettente di questa serie di composti (capitolo 1: “Acetal derivatives as prodrugs of resveratrol”).
La deprotezione completa per rigenerare Resveratrolo è risultata tuttavia piuttosto lenta. Abbiamo quindi deciso di testare nuovi derivati aventi un diverso legame chimico e diversi gruppi sostituenti. Il capitolo 2, “New water-soluble carbamate ester derivatives of resveratrol”, presenta i risultati ottenuti con derivati del Resveratrolo recanti PEG 350 o sostituenti di tipo zuccherino incorporati come carbammato N,N-di-sostituito. Queste molecole presentano il vantaggio di essere più idrosolubili, mantenendo al contempo la stessa capacità di permeazione delle membrane cellulari. Tuttavia, l’elevata stabilità di questi composti è risultata ancora problematica.
La stabilità del legame carbammico può essere modulata variando il numero e caratteristiche dei sostituenti sull’atomo di azoto; abbiamo quindi testato il legame estere carbammato N-mono-sostituito, che ci attendevamo fosse più labile rispetto al suo equivalente di-sostituito. I capitoli 3 e 4 (rispettivamente “N-monosubstituted carbamate ester derivatives of resveratrol” and “Synthesis and evaluation of hydrophilic carbamate ester analogos of resveratrol”) presentano due serie di derivati del Resveratrolo contenenti aminoacidi, brevi oligomeri di glicole etilenico o sostituenti zuccherini collegati allo “scaffold” stilbenico con questo gruppo. La versione N-mono-sostituita del legame estere carbammato presenta un’elevata stabilità in ambiente acido, una buona stabilità a pH neutro e viene idrolizzata con un’opportuna cinetica in sangue di ratto. La stabilità di questi composti dipende in parte dal gruppo sostituente legato all’azoto. Tuttavia la maggior parte di essi ha dimostrato una reattività idonea all’uso come pro-farmaci del Resveratrolo (capitolo 3).
Oltre a subire un rapido metabolismo di fase II, il Resveratrolo è anche poco solubile in acqua. La sua somministrazione è limitata a pillole o all’uso di eccipienti. Derivati del Resveratrolo solubili in acqua potrebbero quindi facilitarne la somministrazione, specialmente se cronica. Nel capitolo 4 presento derivati del Resveratrolo tri- di- e mono-derivatizzati come esteri carbammici N-monosostituiti; in queste molecole il gruppo sostituente è di tipo poliidrossilico (diidrossipropile o 6-deossigalattosio), e conferisce un’elevata solubilità in acqua. I derivati con il galattosio sono sostanzialmente confinati nell’intestino, dove si accumulano in particolare nei tratti finali, subendovi la progressiva perdita dei gruppi protettori. I derivati con il diidrossipropile vengono invece assorbiti dall’intestino. In particolare, i risultati migliori sono stati ottenuti somministrando i derivati mono-sostituiti.
Ho quindi applicato le conoscenze acquisite lavorando con il Resveratrolo allo Pterostilbene, l’analogo 3,5-dimetilato del Resveratrolo. Poiché lo Pterostilbene è ancora poco caratterizzato abbiamo innanzitutto eseguito una dettagliata analisi sulla distribuzione della molecola negli organi dopo la sua somministrazione orale (capitolo 5, “Pharmacokinetics and tissue distribution of pterostilbene in the rat”). I livelli di Pterostilbene negli organi sono risultati molto elevati in paragone a quelli misurati nel sangue. Tuttavia, eccetto che nel cervello, il suo metabolita solfato è risultato la specie più abbondante nei tessuti esaminati. Abbiamo quindi testato una piccola libreria di pro-farmaci dello Pterostilbene basati sul legame carbammico N-monosostituito e amminoacidi naturali. Come ci attendavamo, la stabilità di questi derivati è compresa in un intervallo utile per l’uso come pro-farmaci. L’assorbimento dei derivati recanti amminoacidi apolari è fortemente incrementato (capitolo 6, “Boosting pterostilbene’s effects: a prodrug approach”). Oltre ad un intenso e sostenuto assorbimento intestinale, alcuni precursori si sono distinti per i livelli di Pterostilbene rigenerati nel sangue. Uno di questi composti è stato selezionato come più promettente e la sua distribuzione negli organi dopo somministrazione orale è stata mappata seguendo gli stessi criteri adottati per lo Pterostilbene (descritti nel capitolo 5). Il derivato stesso è stato la specie più abbondante misurata negli organi esaminati, eccetto che nel cervello, mentre i livelli del metabolita solfato erano diminuiti e quelli dello Pterostilbene aumentati nella maggior parte degli organi esaminati. I pro-farmaci possono quindi essere utili strumenti per aumentare la biodisponibilità di alcuni polifenoli.
Nella seconda parte del mio dottorato ho condotto indagini, ancora in corso, su aspetti dei meccanismi cellulari con cui agiscono Resveratrolo e Pterostilbene. A tal scopo abbiamo adottato un duplice approccio, sia in vitro che in vivo, presentati in questa sede in due diversi capitoli, focalizzati in particolare sull’induzione di autofagia e sulla modulazione dei processi cognitivi deteriorati dall’età, rispettivamente.
Infine, nel corso del mio dottorato sono stato coinvolto in altri progetti in corso nel gruppo. Questa partecipazione ha fatto sì che io fossi incluso fra gli autori di tre pubblicazioni, che includo in questa tesi come capitoli 9, 10 ed 11.

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EPrint type:Ph.D. thesis
Tutor:Zoratti, Mario
Data di deposito della tesi:27 January 2015
Anno di Pubblicazione:27 January 2015
Key Words:Resveratrol, Pterostilbene, pharmacokinetics, prodrugs, autophagy, cognitive aging
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Area 05 - Scienze biologiche > BIO/15 Biologia farmaceutica
Struttura di riferimento:Centri > Centro Interdipartimentale di servizi A. Vallisneri
Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:7610
Depositato il:12 Nov 2015 12:29
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