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

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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. β-Cyclodextrin derivatives can also act as cholesterol scavengers to promote cholesterol efflux from cells to extracellular acceptors.

This context has inspired the authors to synthesize and characterize two new cyclodextrin-fluvastatin conjugates representing the first example of cyclodextrin conjugates of statins.

They synthesized 3- and 6-functionalized β-cyclodextrin with fluvastatin through an amide bond. While Fluvastatin is toxic for neuronal cells, Fluvaststatin-cyclodextrin conjugates are non-toxic. The Fluvastatin cyclodextrin conjugates are stable in plasma and mouse brain homogenates. Moreover, the Fluvastain derivatives are well tolerated by cultured neuron cells, and they completely rescue from cell death induced by Aβ oligomers. Overall, the Fluvastain derivatives have potential as therapeutic agents in diseases related to cholesterol dyshomeostasis.

MTT assay was performed on primary neuronal cultures after 48h treatments. Cells were exposed to 2µM Aβ oligomers incubated with or without CD3Flu, CD6Flu at the molar ratio of 1:1. Co-incubations with Flu and β-CD alone were also performed as experimental controls. 

Mariacristina Nicolosi, Francesco Bellia, Maria Laura Giuffrida, Stefania Zimbone, Valentina Oliveri, Graziella Vecchio (2021) Synthesis and biological evaluation of novel β-cyclodextrin-fluvastatin conjugates. Results in Chemistry 100230.

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