http://http://dspace.unitus.it:80 The DSpace digital repository system captures, stores, indexes, preserves, and distributes digital research material. Sun, 19 May 2013 22:08:24 GMT 2013-05-19T22:08:24Z http://hdl.handle.net/2067/1119 Title: Preparazione di antiossidanti a struttura catecolica e di prodotti di interesse biologico di ossifunzionalizzazione benzilica da sostanze fenoliche naturali con sistemi biomimetici (IBX) ed enzimatici (laccasi/HBT) Authors: Crisante, Fernanda Abstract: La ricerca svolta nel triennio di dottorato ha sviluppato metodologie ossidative con reagenti chimici biomimetici ed enzimatici per l’ottenimento di fine chemicals e composti biologicame nte attivi a partire da sostanze presenti negli scarti agroalimentari. Essi, infatti, rappresentano una fonte di molecole di pregio, quali i biofenoli, le cui attività biologiche ne hanno promosso l’utilizzazione in campo nutraceutico, cosmetico e farmaceutico e che possono essere, a loro volta, utilizzati come materiali di partenza per l’ottenimento di nuovi prodotti di interesse industriale. Le metodologie di estrazione ed isolamento di tali fenoli sono già note e ne permettono l’ottenimento per alcuni di essi anche in discrete quantità. La prima parte del lavoro ha previsto la messa a punto di una serie di metodologie di protezione delle molecole in esame. Nello specifico, è stata sviluppata una procedura di metilazione di flavoni impiegando il dimetil carbonato (DMC), un composto ecocompatibile, nel ruolo di solvente/reagente, in sostituzione dei tossici e cancerogeni agenti metilanti di uso comune quali lo ioduro di metile e il dimetilsolfato. Il sistema si è rivelato efficiente, i prodotti metilati, dotati di importanti attività biologiche, sono stati ottenuti con rese quantitative. Successivamente, il DMC è stato impiegato come agente carbossimetilante per la protezione selettiva di funzioni alcoliche presenti nei composti fenolici e come solvente nelle reazioni di acetilazione selettiva degli stessi composti. Sono state messe a punto due metodologie di acetilazione; la prima con anidride acetica in presenza di quantità catalitiche di tricloruro di rutenio e la seconda con cloruro di acetile in assenza di catalizzatore. Quest’ultima procedura è stata estesa per esterificare le funzioni alcoliche di composti fenolici con cloruri di acidi a catena lunga satura e insatura. La maggior parte di queste reazioni è avvenuta con conversioni e rese quantitative e il prodotto target è stato recuperato puro per semplice work-up. Oltre alla metodologia di protezione, sono risultati interessanti anche alcuni dei prodotti ottenuti, in particolare i derivati dell’idrossitirosolo, in quanto molecole antiossidanti dotate di una maggiore lipofilicità e quindi maggiore biodisponibilità rispetto a quelle naturali. L’impiego dei reagenti ossidanti appartenenti alla famiglia dello iodio ipervalente, quali l’IBX e il DMP, ci ha permesso di raggiungere altri importanti obiettivi. Sfruttando la capacità di tali ossidanti di formare la funzione catecolica per inserzione ossidrilica o demetilazione ossidativa, è stato possibile mettere a punto nuove procedure sintetiche dell’idrossitirosolo, una molecola dotata di molteplici attività biologiche, a partire da materiali di partenza presenti negli scarti agroindustriali, quali il tirosolo e l’alcol omovanillico. Tali procedure, per la loro originalità, semplicità, economicità, efficienza e il basso impatto ambientale, sono state oggetto di un brevetto nazionale ed uno internazionale. La sintesi dell’idrossitirosolo è stata presa come metodologia di riferimento per verificare l’efficienza nelle reazioni di inserzione ossidrilica e demetilazione ossidativa dell’IBX supportato su polistirene. Il nuovo reattivo eterogeneo ha mostrato una selettività elevata; è stato recuperato e riutilizzato per dieci volte con un notevole abbattimento dei costi e dell’impatto ambientale del processo ossidativo. Inoltre, sono state sintetizzate altre molecole di pregio quali il piceatannolo e derivati lipofili per sintesi diretta dal trans-resveratrolo, composto presente negli scarti della lavorazione del vino; i flavoni e flavanoni con struttura catecolica, importanti antiossidanti; gli 1-arilisocromani poliossidrilati. Lo studio sulle ossidazioni con IBX è proseguito analizzandone altre potenzialità quali la capacità di deidrogenare in posizione adiacente ad un gruppo carbonilico per sintetizzare flavoni a partire da flavanoni, e la capacità di ossidare la posizione benzilica per indurre l’apertura d’anello di 1-arilisocromani allo scopo di formare importanti fine-chemicals. Gli ultimi e più recenti dati sono relativi all’impiego della catalisi ossidativa enzimatica ricorrendo al sistema O2/laccasi/HBT per ossidare la posizione benzileterea degli 1-arilisocromani e la posizione benzilica delle catechine. I risultati ottenuti sono stati soddisfacenti. In particolare, nell’ossidazione delle catechine, il sistema catalitico ha mostrato una stereoselettività nell’inserzione ossidrilica in posizione C-4 che mima quanto avviene in natura ad opera di batteri endofiti delle piante del tè.; The research activity of this PhD course has developed oxidative methodologies by chemical and enzymatic reagents to obtain fine-chemicals and high add-value molecules from natural phenols present in agroindustrial wastes as starting materials. A first aim has been the flavones methylation by using dimethyl carbonate (DMC) as environmentally benign substitute for hazardous and toxic reagents such as methyl halides and methyl sulfate. Reactions proceeded with complete substrate conversion and yield; final products possess many biological and pharmacological activities. Subsequently, DMC has been used as well as reagent for the selective carbomethoxylation of aliphatic alcoholic chain of phenols and solvent for the selective acylation of these compounds. Two methodologies of acylation have been developed; the first, by acetic anhydride in the presence of a catalytic amount of RuCl3 as catalyst and the second, by acetyl chloride in DMC without any catalyst. This simple and cheap last procedure has been extended to the esterification of these compounds by using acyl chlorides with long saturated or unsaturated chains. All corresponding products were obtained in satisfactory conversions and yields. Between the obtained compounds, lipophilic derivatives of hydroxytyrosol are of particular interest. Important results have been obtained by using hypervalent iodine reagents of oxidation as the 2- iodobenzoic acid (IBX) and Dess-Martin Reagent (DMP). First, two convenient synthetic strategies to prepare hydroxytyrosol as well its lipophilic derivatives have been developed from commercially available, cheap natural phenols such as tyrosol and homovanillyl alcohol. These syntheses, for their originality, simplicity, economic validity, efficiency and ecofriendly character, have been deposited for a national and an international patent. Hydroxytyrosol synthesis has been employed also to verify the efficiency of polymer-supported IBX through the oxidative insertion of a hydroxyl and the demethylation reactions of phenolic compounds. After the first oxidation, the polymeric reagent was recovered, regenerated and reused for ten oxidation reactions without lack of efficiency to give the final products in excellent yields achieving economic and environmentally benefits. Other important molecules have been synthesized by using the oxidative chemistry of IBX: piceatannol and its lipophilic derivates starting to trans-resveratrol; antioxidant flavones and flavanones with catecholic structure; polyhydroxylated 1-arilisochromans. Again, we have applied IBX for the dehydrogenation of carbonylic groups to synthesize flavones starting to flavanones and for the oxidation of benzylic position of 1-arylisochromans to obtain fine-chemicals. Finally, the chemistry of enzymatic catalytic system O2/laccases/HBT has been optimized to oxidize benzyl ethereal position of 1-arylisochromans and benzylic position of catechins. Results have been satisfactory; the catalytic system has been selective and efficient to insert an oxygen atom in C-4 position miming the natural oxidation performed by bacteria contained in tea plants. Description: Dottorato di ricerca in scienze ambientali Wed, 18 Feb 2009 23:00:00 GMT http://hdl.handle.net/2067/1119 2009-02-18T23:00:00Z http://hdl.handle.net/2067/1296 Title: A Convenient and Safe O-Methylation of Flavonoids with Dimethyl Carbonate (DMC) Authors: Bernini, Roberta; Crisante, Fernanda; Ginnasi, Maria Cristina Abstract: Dietary flavonoids exhibit beneficial health effects. Several epidemiological studies have focused on their biological activities, including antioxidant, antibacterial, antiviral, anti-inflammatory and cardiovascular properties. More recently, these compounds have shown to be promising cancer chemopreventive agents in cell culture studies. In particular, O-methylated flavonoids exhibited a superior anticancer activity than the corresponding hydroxylated derivatives being more resistant to the hepatic metabolism and showing a higher intestinal absorption. In this communication we describe a convenient and efficient procedure in order to prepare a large panel of mono- and dimethylated flavonoids by using dimethyl carbonate (DMC), an ecofriendly and non toxic chemical, which plays the role of both solvent and reagent. In order to promote the methylation reaction under mild and practical conditions, 1,8-diazabicyclo[5.4.0]undec-7- ene (DBU) was added in the solution; methylated flavonoids were isolated in high yields and with a high degree of purity. This methylation protocol avoids the use of hazardous and high toxic reagents (diazomethane, dimethyl sulfate, methyl iodide). Description: L'articolo è disponibile sul sito dell'editore: www.mdpi.com Fri, 31 Dec 2010 23:00:00 GMT http://hdl.handle.net/2067/1296 2010-12-31T23:00:00Z http://hdl.handle.net/2067/1571 Title: Synthesis of a novel ester of hydroxytyrosol and lipoic acid exhibiting an antiproliferative effect on human colon cancer HT-29 cells Authors: Bernini, Roberta; Crisante, Fernanda; Merendino, Nicolò; Molinari, Romina; Soldatelli, Maria Chiara; Velotti, Francesca Abstract: A novel hydroxytyrosol-lipoic acid derivative has been synthesized. Key steps are an esterification reaction between tyrosol and -lipoic acid derivatives and a regioselective aromatic hydroxylation of the monohydroxylated ester performed by 2-iodoxybenzoic acid (IBX) followed by an in situ reduction with sodium dithionite (Na2S2O4). The novel ester exhibited an antiproliferative effect on the human colorectal adenocarcinoma HT-29 cell line significantly more potent than its parent compounds Thu, 31 Dec 2009 23:00:00 GMT http://hdl.handle.net/2067/1571 2009-12-31T23:00:00Z http://hdl.handle.net/2067/1581 Title: Synthesis of a novel ester of hydroxytyrosol and lipoic acid exhibiting an antiproliferative effect on human colon cancer HT-29 cells Authors: Bernini, Roberta; Crisante, Fernanda; Merendino, Nicolò; Molinari, Romina; Soldatelli, Maria Chiara; Velotti, Francesca Abstract: A novel hydroxytyrosol-lipoic acid derivative has been synthesized. Key steps are an esterification reaction between tyrosol and cJipoic acid derivatives and a regioselective aromatic hydroxylation ofthe monohydroxylated ester performed by 2-iodoxybenzoic acid (IBX) followed by an in situ reductionw ith sodium dithionite (Na2S2O4T).h e novel estere xhibited an antiproliferative effect on the human colorectal adenocarcinoma HT-29 cell line signifrcantly more potent than its parent compounds. Thu, 31 Dec 2009 23:00:00 GMT http://hdl.handle.net/2067/1581 2009-12-31T23:00:00Z http://hdl.handle.net/2067/1572 Title: New and efficient syntheses of hydroxytyrosol and its lipophilic derivatives Authors: Barontini, Maurizio; Crisante, Fernanda; Fabrizi, Giancarlo; Mincione, Enrico Abstract: New and efficient oxidative procedures to synthesize hydroxytyrosol and its lipophilic derivatives are described. Starting materials are available and natural compounds such as tyrosol and homovanillyl alcohol. The oxidants of choice are both homogeneous and heterogeneous 2-iodoxybenzoic acid (IBX and IBX-polystyrene) able to perform the aromatic hydroxylation and the oxidative demethylation of phenolic compounds with a chemo and regioselectivity similar to that of the polyphenol oxidase and cytochrome P450. The reactions proceed quickly and the final products are isolated in good yields and high purity. After the first oxidation, IBX-polystyrene is recovered by simple filtration, regenerated and reused for more cycles of oxidation reactions without loss of efficiency Thu, 31 Dec 2009 23:00:00 GMT http://hdl.handle.net/2067/1572 2009-12-31T23:00:00Z http://hdl.handle.net/2067/1879 Title: Dimethyl carbonate: an environmentally friendly solvent for hydrogen peroxide (H2O2)/methyltrioxorhenium (CH3ReO3, MTO) catalytic oxidations Authors: Bernini, Roberta; Mincione, Enrico; Barontini, Maurizio; Crisante, Fernanda; Fabrizi, Giancarlo; Gambacorta, Augusto Abstract: Environmentally friendly oxidations of various organic compounds with the hydrogen peroxide (H2O2)/methyltrioxorhenium(CH3ReO3, MTO) catalytic system have been described in dimethyl carbonate (DMC), a cheap commercially available and benign chemical having interesting solvating properties, low toxicity and high biodegradability. Oxidations proceeded with good conversions and in good yields. Spectrophotometric analysis demonstrated that the [CH3ReO(O–O)2] complex was formed in DMC and that it was stable for several days at room temperature. Description: L'articolo è disponibile sul sito dell'editore: http://www.sciencedirect.com Sun, 31 Dec 2006 23:00:00 GMT http://hdl.handle.net/2067/1879 2006-12-31T23:00:00Z http://hdl.handle.net/2067/1881 Title: Chemoselective and efficient carboxymethylation of the alcoholic chain of phenols by dimethyl carbonate (DMC). Authors: Bernini, Roberta; Mincione, Enrico; Crisante, Fernanda; Barontini, Maurizio; Fabrizi, Giancarlo; Gentili, Patrizia Abstract: The efficiency of dimethyl carbonate (DMC) as chemoselective carbomethoxylating agent of the alcoholic chain of phenols has been investigated. In the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sulfuric acid as catalysts. New carbomethoxylated phenolic compounds were obtained in quantitative yields. A new efficient derivatization of the aliphatic alcoholic chain of the precious natural hydroxytyrosol is described, which increases the lipophilicity of the hydroxytyrosol. The antioxidant activity of this new carboxymethylated hydroxytyrosol 8 has been investigated using DPPH radical scavenging test. The results showed that this new compound has an antioxidant activity similar to hydroxytyrosol. Description: L'articolo è disponibile sul sito dell'editore: http://www.sciencedirect.com Sun, 31 Dec 2006 23:00:00 GMT http://hdl.handle.net/2067/1881 2006-12-31T23:00:00Z