In our effort to develop multifunctional compounds that cotarget beta-amyloid oligomers (AbetaOs), cell membrane/lipid rafts (CM/LR), and oxidative stress, a series of bivalent multifunctional Abeta oligomerization inhibitors (BMAOIs) containing cholesterol and curcumin were designed, synthesized, and biologically characterized as potential treatments for Alzheimer's disease (AD). The in vitro assay results established that the length of spacer that links cholesterol and curcumin and the attaching position of the spacer on curcumin are important structural determinants for their biological activities. Among the BMAOIs tested, 14 with a 21-atom-spacer was identified to localize to the CM/LR of human neuroblastoma MC65 cells, to inhibit the formation of AbetaOs in MC65 cells, to protect cells from AbetaOs-induced cytotoxicity, and to retain antioxidant properties of curcumin. Furthermore, 14 was confirmed to have the potential to cross the blood-brain barrier (BBB) as demonstrated in a Caco-2 cell model. Collectively, these results strongly encourage further optimization of 14 as a new hit to develop more potent BMAOIs.

In a continuing effort to develop multifunctional compounds as potential treatment agents for Alzheimer’s disease (AD), a series of bivalent ligands containing curcumin and cholesterylamine were designed, synthesized, and biologically characterized. Biological characterization supported earlier results that the spacer length and its attachment position on curcumin are essential structural determinants for biological activity in this class. Compounds with a spacer length of 17 to 21 atoms exhibited optimal neuroprotection in human neuroblastoma MC65 cells with submicromolar potency. These compounds inhibited the formation of amyloid-β oligomers (AβOs) and exhibited antioxidative activities in MC65 cells. Bivalent ligand 8, with its spacer (length of 17 atoms) connected at the methylene carbon between the two carbonyls of curcumin moiety is the most potent with an EC50 of 0.083 ± 0.017 μM. In addition, 8 formed complex with biometals, such as Cu, Fe and Zn. Collectively, the results strongly support our assertion that these compounds are designed bivalent ligands with potential as multifunctional and neuroprotective agents.

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