Bivalent Ligands Targeting Multiple Pathological Factors Involved in Alzheimer's Disease

Abstract

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.

Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease

“…As shown in Table 1, overall, the results of the six bivalent compounds are in agreement with our previous studies and show that compounds with 17-atom spacers are more potent than those with a 21-atom spacer (~ 3–6 times more potent). 29, 31 Specifically, 17MN and 21MN rescued MC65 cells with an EC 50 being 56.50 ± 9.08 and 212.28 ± 54.87 nM, respectively, consistent with our previously reported results. 31 Surprisingly, 21MO showed a significantly reduced potency (1848.67 ± 325.13 nM) compared our previously reported compound with a 21-atom spacer but different spacer composition.…”

“…29, 31 Specifically, 17MN and 21MN rescued MC65 cells with an EC 50 being 56.50 ± 9.08 and 212.28 ± 54.87 nM, respectively, consistent with our previously reported results. 31 Surprisingly, 21MO showed a significantly reduced potency (1848.67 ± 325.13 nM) compared our previously reported compound with a 21-atom spacer but different spacer composition. 33 This suggests that the nature of the spacer does play an essential role in the observed biological activities of these bivalent compounds.…”

“…Studies from our group and others have demonstrated that this cellular assay is a suitable screening model to test small molecule compounds with potential protective activities. 31, 33, 42–45 Thus, we first tested the six bivalent compounds in MC65 cells for their potency to rescue these cells from cytotoxicity induced by TC removal. As shown in Table 1, overall, the results of the six bivalent compounds are in agreement with our previous studies and show that compounds with 17-atom spacers are more potent than those with a 21-atom spacer (~ 3–6 times more potent).…”

“…29, 31 To understand the impact of the membrane anchor on the biology, we retained the spacer composition of 17MN and varied the anchor moiety within the set of structures. As shown in Figure 2, three of our previously studied membrane-anchoring molecules were employed for this study: cholesterol, cholesterylamine and diosgenin.…”

Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer’s Disease

“…[12, 13] Our results demonstrated that the bivalent compounds exhibit significantly improved neuroprotection compared to the “war head” and the CM/LR anchor alone, or the combination of these two. Furthermore, we have demonstrated that the spacer length between the “war head” and the anchorage moiety is critical for neuroprotection.…”