suppressor activity can be stimulated to eradicate tumor cells. In tumor cells, its endogenous inhibitor, the humanMDM2 protein, effectively inhibits the p53 activity. The interaction site between MDM2 and p53 proteins is mediated by a well-defined pocket in MDM2 and a short helix from p53, making this site attractive for the design of small-molecule inhibitors to block the MDM2-p53 protein-protein interaction. Reactivation of p53 by blocking the MDM2-p53 interaction using a small-molecule inhibitor is being pursued as a new cancer therapeutic strategy.1-2 The reaction of 1,3-dipolar cycloaddition (1,3-DC) represents a valid approach to a variety of heterocycles: a highlight of its power in synthesis is its use to construct the five-membered ring. In particular, the 1,3-dipolar cycloadditions of opportune nitrones3 with alkenes afforded isoxazolidines, which are interesting intermediates for the synthesis of α-amino alcohols and alkaloids or, more recently, of cyclic and bicyclic 4’- aza-analogues of 2’,3’-dideoxynucleosides, isoxazolidinyl nucleosides with antiviral or anticancer activity.4 In the present work, the synthesis of spiro-compounds containing both indole portions and isoxazolidine rings will be illustrated. The synthesis was realized by microwave- assisted 1,3 dipolar cycloaddition between nitrones of indole derivatives and vinyl- substrates. The choice of the substrates and substituents and the study of trend of reactions were supported by docking and computational calculations.
Spiroisoxazolidines as Promising Anticancer Agents through Protein/non-Peptide Small- Molecule Interactions
NARDI M;
2016-01-01
Abstract
suppressor activity can be stimulated to eradicate tumor cells. In tumor cells, its endogenous inhibitor, the humanMDM2 protein, effectively inhibits the p53 activity. The interaction site between MDM2 and p53 proteins is mediated by a well-defined pocket in MDM2 and a short helix from p53, making this site attractive for the design of small-molecule inhibitors to block the MDM2-p53 protein-protein interaction. Reactivation of p53 by blocking the MDM2-p53 interaction using a small-molecule inhibitor is being pursued as a new cancer therapeutic strategy.1-2 The reaction of 1,3-dipolar cycloaddition (1,3-DC) represents a valid approach to a variety of heterocycles: a highlight of its power in synthesis is its use to construct the five-membered ring. In particular, the 1,3-dipolar cycloadditions of opportune nitrones3 with alkenes afforded isoxazolidines, which are interesting intermediates for the synthesis of α-amino alcohols and alkaloids or, more recently, of cyclic and bicyclic 4’- aza-analogues of 2’,3’-dideoxynucleosides, isoxazolidinyl nucleosides with antiviral or anticancer activity.4 In the present work, the synthesis of spiro-compounds containing both indole portions and isoxazolidine rings will be illustrated. The synthesis was realized by microwave- assisted 1,3 dipolar cycloaddition between nitrones of indole derivatives and vinyl- substrates. The choice of the substrates and substituents and the study of trend of reactions were supported by docking and computational calculations.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
