Bivalent ligands targeting multiple pathological factors involved in Alzheimer's disease.

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 EC(50) 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.