Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer’s disease

Abstract

In an effort to combat the multifaceted nature of Alzheimer’s disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD.

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.…”

“…24, 26 Specifically, the optimal spacer length ranges from 17 to 21 atoms in our models. 29, 31, 33 Notably, our studies suggested that the spacer length and the anchor moiety of the bivalent compounds may determine the sub-cellular localization of these bivalent compounds with different, yet overlapping, biological activities. 28, 30 In addition, bivalent compounds with different spacers showed different profiles with respect to their biometal chelating properties.…”

“…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.…”

“…38, 39 Therefore, incorporation of diosgenin into our molecular design may offer a double role: anchoring to the membrane and neuroprotective activity, which was clearly supported by the results of our recent studies. 29 …”

Plant Adaptogens: Natural Medicaments for 21stCentury?

“…In an effort to control the multifaceted nature of Alzheimer's disease progression, a series of multifunctional, bivalent compounds containing curcumin ( 3.1 ), diosgenin ( 3.2 ) and caprospinol ( 3.3 ) were designed, developed and subjected to investigation (Figure ). Biological characterization of these compounds for protective activity in MC65 cells was confirmed.…”