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New potential sodium-glucose co-transporters sugar-based inhibitors for the treatment of diabetes
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Resumo(s)
A small library of C-glucosyl dihydrochalcones and their aglycones, chalcones and dihydrochalcones, were synthesized aiming at preparing new C-glucosyl analogues of phlorizin, a well-known non-selective sodium-glucose co-transporter inhibitor, bearing different substituents on the dihydrochalcone moiety. Chalcones were prepared by conventional aldol condensation methods and also by microwave-assisted synthesis. The yields using the latter were relatively similar to those obtained by conventional methods (70-95%) but it was possible to decrease the reaction time from 24 to 1 h. Dihydrochalcones were obtained in 90-99% by in situ hydrogenation using the system Et3SiH/Pd-C, a method that was used for the first time in this family of compounds, that revealed very promising and simple to run. C-Glucosylation of dihydrochalcones was investigated with the catalyst TMSOTf and using 2,3,4,6-tetra-O-benzyl--D-glucopyranose as glycosyl donor, instead of a donor with a more effective leaving group at the anomeric position, e.g. trichloroacetimidate, to decrease the number of reaction steps. The C-glucosylation proceeded smoothly with yields ranging from 40-47% and the following debenzylation by in situ hydrogenation (80- 98% yield) afforded the C-glucosyl dihydrochalcones. Cytoxicity of chalcones, dihydrochalcones and C-glucosyl dihydrochalcones was evaluated in HEK293 cells and no significant toxicity was found for those compounds bearing three hydroxyl groups in ring A. Conversely, chalcones and dihydrochalcones bearing one or two hydroxyl groups on ring B showed significant cytoxicity in the same cell line. Two stable cell lines were generated, HEK293-SGLT1 and HEK293-SGLT2, and the two stable clones showing the highest expression by Western Blot and RT-PCR were used to evaluate the inhibitory properties of chalcones, dihydrochalcones, and C-glucosyl dihydrochalcones as well as to determine their IC50 values towards SGLT1 and SGLT2 proteins. Results showed that chalcones and dihydrochalcones are able to partially inhibit SGLT1 and SGLT2 without showing significant selectivity towards with SGLT1 or SGLT2. On the other hand, C-glucosyl dihydrochalcones inhibit both SGLT1 and SGLT2 at 100 M but showed a > 500-fold SGLT2 selectivity. IC50 of these molecules were much better than those of phlorizin, but slightly worse than the commercial drug dapagliflozin. Nevertheless, changing from the O-glucoside phlorizin to its C-glucosyl analog, it was possible to increase its inhibitory ability as well its selectivity.
Descrição
Tese de doutoramento, Química (Química Orgânica), Universidade de Lisboa, Faculdade de Ciências, 2015
Palavras-chave
Diabetes C-glucosil Glucose - absorção Teses de doutoramento - 2015