Institute of Crystallography - CNR

Synthesis and biological evaluation of novel beta-cyclodextrin-fluvastatin conjugates

Drugs that may regulate lipid metabolism and lower cholesterol, such as statins (drugs that reduce de novo cholesterol synthesis) or cyclodextrins (that promote cholesterol removal), are currently investigated as potential therapeutics for neuronal disorders like Alzheimer’s and Niemann Pick type C disease. Fluvastatin is a member of the statin class widely used in preventing heart diseases as it lowers cholesterol and other lipids. ?-Cyclodextrin derivatives can also act as cholesterol scavengers to promote cholesterol efflux from cells to extracellular acceptors. This context has inspired us to synthesize and characterize two new cyclodextrin-fluvastatin conjugates representing the first example of cyclodextrin conjugates of statins. We synthesized 3- and 6-functionalized ?-cyclodextrin with fluvastatin through an amide bond. We studied the stability, cytotoxicity and protective activity in cells of the new derivatives. We observed that the Fluvastatin cyclodextrin conjugates are stable in plasma and mouse brain homogenates. Moreover, we found that the Fluvastain derivatives are well tolerated by cultured neuron cells, and they completely rescue from cell death induced by A? oligomers. Overall, the Fluvastain derivatives have potential as therapeutic agents in diseases related to cholesterol dyshomeostasis.

Results in chemistry
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Mariacristina Nicolosi, Francesco Bellia, Maria Laura Giuffrida, Stefania Zimbone, Valentina Oliveri,Graziella Vecchio