Obesity is a complex disease characterized by excessive body fat. It is considered a risk factor for chronic disorders and cardiovascular diseases, cancer, osteoarthritis, and hypertension. The incidence of obesity is frequently linked to the incidence of type 2 diabetes, a metabolic disease characterized by dysfunctional insulin hormone and high blood glucose levels. It is also noteworthy that hyperglycemia associated with type 2 diabetes is characterized by increased production of reactive oxygen species, causing oxidative tissue damage. Some therapeutic approaches to the management of obesity and type 2 diabetes are related to the inhibition of metabolic enzymes: pancreatic lipase, the enzyme responsible for the hydrolysis of free fatty acid; α-amylase and α-glucosidase, carbohydrate hydrolyzing enzymes, whose inhibition is a well-established strategy to manage hyperglycemia. Approved anti-obesity and hypoglycemic drugs are, respectively, Orlistat and Acarbose, showing, however, some side effects. Hence, increasing interest has turned to natural products and their analogues to find new and safe enzyme inhibitors with low or without side effects. This thesis reports on phenolic compounds and their inspired analogues as new potential inhibitors of metabolic enzymes. Magnolia species contain several compounds with different structures and biological activities. The neolignans magnolol and honokiol have been extensively investigated for their wide biological effects. Consequently, nowadays there is an increasing interest in synthesizing new analogues inspired by the two neolignans to enhance their biological effects. Thus, the first phase of this research aimed to synthesize nitrogenated analogues inspired by magnolol and honokiol as potential lipase inhibitors. Obovatol, a lesser-studied biphenyl ether compound isolated from the bark and leaves of Magnolia obovata, exhibits promising biological activity, even if its low bioavailability hinders extensive research. For this reason, the research activity was focused on developing a convenient access to obovatol and its analogues by total chemical synthesis and to evaluate their inhibitory activity towards carbohydrate hydrolyzing enzymes. In addition to biphenyl and biaryl ether compounds, Magnolia species also contain oligomeric compounds. Among them, honokiol dimer Houpulin B has been reported with 0.003% yield extraction from the roots of M. officinalis and consequently, few studies have been carried out to evaluate its biological activity. For this reason, the main challenge was developing and carrying out a chemical synthesis. Thus, the research project was devoted to the optimization and biomimetic synthesis of Houpulin B and two new dimers not naturally occurred: magnolol dimer and honokiolmagnolol dimers. The evaluation of the inhibitory activity towards pancreatic lipase, α-glucosidase and α-amylase of the three natural products and their bioinspired compounds (nitrogenated magnolol and honokiol analogues, biaryl or thiol ether compounds, and oligomeric products) was performed with in vitro biochemical assays, kinetic analysis, fluorescence spectroscopy, circular dichroism experiments and in silico analysis. This research contributes to identify key structural features in the search for more suitable candidates for metabolic enzyme inhibitors, thus considering these natural compounds and their analogues as interesting scaffolds for future studies.
L’obesità è una patologia caratterizzata da un eccesso di grasso corporeo ed è associata ad un aumento del rischio di disturbi cronici e malattie cardiovascolari, cancro, osteoartrite e ipertensione. L’incidenza dell’obesità è spesso correlata a quella del diabete di tipo 2, una malattia metabolica caratterizzata dalla disfunzione dell’ormone insulinico e da elevati livelli di glucosio nel sangue. Inoltre, l’iperglicemia associata al diabete di tipo 2 è caratterizzata da un’aumentata produzione di specie reattive dell’ossigeno che causano danni ossidativi ai tessuti. L’inibizione degli enzimi metabolici è considerata un valido approccio terapeutico per il trattamento dell’obesità e del diabete di tipo 2. L’inibizione della lipasi pancreatica, enzima responsabile dell’idrolisi degli acidi grassi liberi a partire dai trigliceridi è utile nel trattamento dell’obesità, mentre l’inibizione di α-amilasi e α-glucosidasi, enzimi che idrolizzano i carboidrati, è una strategia consolidata per la gestione del diabete. L’orlistat e l’acarbosio sono rispettivamente farmaci antiobesità e ipoglicemici che tuttavia mostrano diversi effetti collaterali. Per questo motivo, un crescente interesse è rivolto ai prodotti naturali e ai loro analoghi per lo sviluppo di nuovi inibitori enzimatici con effetti collaterali ridotti o assenti. Il focus della presente tesi si basa sui composti fenolici e i loro analoghi come nuovi potenziali inibitori degli enzimi metabolici. La Magnolia è una pianta ricca di numerosi composti con diverse strutture e attività biologiche e, tra questi, i neolignani magnololo e honokiolo sono stati studiati per le loro proprietà biologiche. Al giorno d’oggi c’è un crescente interesse per la sintesi di nuovi analoghi inspirati ai due neolignani per incrementare le proprietà biologiche. Pertanto, la prima fase di questa ricerca ha avuto come obiettivo la sintesi di analoghi azotati ispirati al magnololo e all’honokiolo come potenziali inibitori della lipasi. L’obovatolo è un difeniletere isolato dalla corteccia e dalle foglie della Magnolia obovata. La scarsa biodisponibilità ha ridotto il numero degli studi sebbene il composto presenta un’attività promettente. Pertanto, l’attività di ricerca si è concentrata sulla sintesi dell’obovatolo e di una libreria di suoi analoghi mediante sintesi chimica totale e la valutazione della loro attività inibitoria nei confronti di α-glucosidasi e α-amilasi. Oltre ai composti bifenilici e biarilici, la specie della Magnolia contiene anche composti oligomerici come Houpulin B, dimero dell’honokiolo isolato dalle radici della Magnolia officinalis con una resa dello 0.003%. Tuttavia, solo pochi studi sono stati condotti per valutarne la sua attività biologica. Per questo motivo, la sfida principale è stata l’ottimizzazione e la sintesi biomimetica dell’houpulin B e di due nuovi dimeri non presenti in natura: il dimero del magnololo e il dimero misto di magnololo e honokiolo. La valutazione dell’attività inibitoria nei confronti della lipasi pancreatica, α-glucosidasi e α-amilasi dei tre composti naturali e dei loro analoghi (analoghi nitrogenati del magnololo e honokiolo, composti biarilici o tioeterei e prodotti oligomerici) è stata realizzata con saggi biochimici in vitro, studi di cinetica, spettroscopia di fluorescenza, esperimenti di dicroismo circolare e analisi in silico. Questo studio contribuisce all’identificazione delle caratteristiche strutturali chiave per la ricerca di potenziali candidati come inibitori degli enzimi metabolici considerando questi composti naturali e i loro analoghi come interessanti scaffold per studi futuri.
Dai polifenoli naturali agli analoghi sintetici bioattivi / Sciacca, Claudia. - (2023 Dec 19).
Dai polifenoli naturali agli analoghi sintetici bioattivi.
SCIACCA, CLAUDIA
2023-12-19
Abstract
Obesity is a complex disease characterized by excessive body fat. It is considered a risk factor for chronic disorders and cardiovascular diseases, cancer, osteoarthritis, and hypertension. The incidence of obesity is frequently linked to the incidence of type 2 diabetes, a metabolic disease characterized by dysfunctional insulin hormone and high blood glucose levels. It is also noteworthy that hyperglycemia associated with type 2 diabetes is characterized by increased production of reactive oxygen species, causing oxidative tissue damage. Some therapeutic approaches to the management of obesity and type 2 diabetes are related to the inhibition of metabolic enzymes: pancreatic lipase, the enzyme responsible for the hydrolysis of free fatty acid; α-amylase and α-glucosidase, carbohydrate hydrolyzing enzymes, whose inhibition is a well-established strategy to manage hyperglycemia. Approved anti-obesity and hypoglycemic drugs are, respectively, Orlistat and Acarbose, showing, however, some side effects. Hence, increasing interest has turned to natural products and their analogues to find new and safe enzyme inhibitors with low or without side effects. This thesis reports on phenolic compounds and their inspired analogues as new potential inhibitors of metabolic enzymes. Magnolia species contain several compounds with different structures and biological activities. The neolignans magnolol and honokiol have been extensively investigated for their wide biological effects. Consequently, nowadays there is an increasing interest in synthesizing new analogues inspired by the two neolignans to enhance their biological effects. Thus, the first phase of this research aimed to synthesize nitrogenated analogues inspired by magnolol and honokiol as potential lipase inhibitors. Obovatol, a lesser-studied biphenyl ether compound isolated from the bark and leaves of Magnolia obovata, exhibits promising biological activity, even if its low bioavailability hinders extensive research. For this reason, the research activity was focused on developing a convenient access to obovatol and its analogues by total chemical synthesis and to evaluate their inhibitory activity towards carbohydrate hydrolyzing enzymes. In addition to biphenyl and biaryl ether compounds, Magnolia species also contain oligomeric compounds. Among them, honokiol dimer Houpulin B has been reported with 0.003% yield extraction from the roots of M. officinalis and consequently, few studies have been carried out to evaluate its biological activity. For this reason, the main challenge was developing and carrying out a chemical synthesis. Thus, the research project was devoted to the optimization and biomimetic synthesis of Houpulin B and two new dimers not naturally occurred: magnolol dimer and honokiolmagnolol dimers. The evaluation of the inhibitory activity towards pancreatic lipase, α-glucosidase and α-amylase of the three natural products and their bioinspired compounds (nitrogenated magnolol and honokiol analogues, biaryl or thiol ether compounds, and oligomeric products) was performed with in vitro biochemical assays, kinetic analysis, fluorescence spectroscopy, circular dichroism experiments and in silico analysis. This research contributes to identify key structural features in the search for more suitable candidates for metabolic enzyme inhibitors, thus considering these natural compounds and their analogues as interesting scaffolds for future studies.File | Dimensione | Formato | |
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PhD thesis_Claudia Sciacca_From natural polyphenols to synthetic bioactive analogues.pdf
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