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• W2442210080 abstract "Plant polyphenols are a vast family of natural compounds present in many foods and drinks. Many of them have noteworthy biological properties. Resveratrol, for example, can help prevent cardiovascular disease in humans, because it is able to lower blood pressure and lipid peroxidation, to induce vasodilatation and to reduce platelet aggregation. Moreover, resveratrol has antioxidant, anti-inflammatory, and anti-atherosclerotic properties, resulting in protection of the cardiovascular system, improvement of age-related cognitive decline and prevention and therapy of cancer. These potential positive effects are hampered by the low bioavailability of this compound and of polyphenols in general. As a result of a low level of absorption and a rapid metabolism in intestinal and liver cells, only small amounts of polyphenols are found in the bloodstream, and then mostly as metabolites. The major aim of my doctorate work has been the development of “pro-drugs”, resistant to metabolism during absorption and capable of regenerating the natural compound thanks to the action of ubiquitous enzymes. Resveratrol was chosen as model polyphenol. The project is carried out in collaboration with a group of organic chemists who synthesise the compounds and also contribute analytical know-how.Since polyphenols generally have a low solubility in water, and solubility is a key factor contributing to the bioavailability of a compound, a first resveratrol derivative was synthesised in which succinyl linkers connected resveratrol hydroxyls on one side and glucose residues on the other via carboxyester bonds. Pharmacokinetic studies with this compound showed that the levels and the composition of the metabolite mix in the bloodstream were the same as those obtained using resveratrol itself. This suggested that the compound was hydrolysed to resveratrol in the gastro-intestinal tract, before absorption. The carboxyester bond system thus turned out to be too labile in vivo, and therefore of limited usefulness. Other bond systems, such as the ether and sulfonate linkages, proved on the contrary to be too stable We therefore turned to other functionalities. In one approach the acetal bond system was used to link protective/solubilising groups to resveratrol hydroxyls. This type of protecting group is hydrolysed under acid conditions, but turned out to be rather too stable for use in vivo. Ex vivo and in vivo experiments with a series of acetal derivatives bearing short oligo-ethylene glycol chains however allowed us to evaluate and appreciate the positive effect this type of substituents can have on the absorption process.In the search for a protective functionality with ideal stability characteristics, we then turned to yet another, more labile, bond type, which cannot be specified here. To confer water solubility, polyhydroxylated moieties or PEG chains were introduced via this bond system. The work has so far led to satisfactory levels of absorption with two regioisomeric mono-substituted derivatives: uM levels of resveratrol-containing molecules were measured in blood samples, persisting for hours. However, the two free hydroxyl groups in these compounds are targets for glucuronosyltransferases, which largely modify them before the regeneration of resveratrol can be completed. A new approach has now been adopted, incorporating the positive aspects which have emerged from the investigation of acetal derivatives. In these new compounds short oligo-ethyleneglycol chains are linked to all three hydroxyl groups of resveratrol to improve absorption while offering protection. These constructs may be expected to be well absorbed (depending on chain length) and to hydrolyse with suitable kinetics. Only preliminary results with one compound are available at the time this thesis is submitted.During my doctorate I had the opportunity to spend a six-month period in the laboratory of prof. E. Mervaala at the Institute of Biomedicine of the University of Helsinki, Finland. There I performed a preliminary study on the possible positive effects of resveratrol and caloric restriction against sunitinib-induced cardiotoxicity and renal damage in spontaneously hypertensive rats, using normotensive WKY rats as control. Sunitinib is a tyrosine kinase inhibitor (TKI). The results did not reveal statistically significative differences between control and treated rats. Further experiments will be needed before a definite conclusion can be reached.Finally, it should be mentioned that in a side project I participated in studies on the metabolism of polyphenols by cultured cells. Work with monolayers of colonic Caco-2 cells revealed a remarkable heterogeneity in the expression of Phase II metabolism enzymes (sulfo- and glucuronosyl-transferases) within the same cell line. It was however possible to regenerate a uniform activity in the different populations by cultivating the cells with low concentrations of a xenobiotic compound (in our case quercetin)." @default.
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• W2442210080 date "2012-01-30" @default.
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• W2442210080 title "Resveratrol, a natural molecule against hypertension and cardiovascular diseases: development of prodrugs to enhance its bioavailability" @default.
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