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

Abstract

Bivalent compounds anchoring in different manners to the membrane were designed and biologically characterized to understand the contribution of the anchor moiety to their biological activity as neuroprotectants for Alzheimer’s disease. Our results established that the anchor moiety is essential and we identified a preference for diosgenin, as evidenced by 17MD. Studies in primary neurons and mouse brain mitochondria also identified 17MD as exhibiting activity on neuritic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondria. Significantly, our studies demonstrated that the integrated bivalent structure is essential to the observed biological activities. Further studies employing bivalent compounds as probes in a model membrane also revealed the influence of the anchor moiety on how they interact with the membrane. Collectively, our results suggest diosgenin to be an optimal anchor moiety, providing bivalent compounds with promising pharmacology that have potential applications for Alzheimer’s disease.

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

“…Oxidative Medicine and Cellular Longevity [27,58]. The results showed a clear structural preference for the introduction of the methylene carbon between diosgenin and curcumin.…”

“…Their mechanism of action involves antioxidant activity and inhibitory effects on amyloid-β oligomer formation by directly binding to Aβ [58]. Additionally, DG can act as a membrane-anchoring moiety to improve the access to the cell membrane for the conjugates, suggesting that DG is a novel anchor that can facilitate the multifunctional role of bivalent conjugates for further development as potential therapeutic agents for AD treatment [27]. Recently, Yang et al synthesized a series of multifunctional DG derivatives and evaluated their effect from Aβ-induced damage in PC12 cells and improved learning and memory impairments in Aβ-injected mice.…”

“…Numerous studies have demonstrated that DG and its derivatives have preventive and therapeutic effects against various neurological disorders. Animal experiments have shown that DG is active in the treatment of nervous system diseases such as Parkinson's disease and Alzheimer's disease [25][26][27].…”

Design and characterization of bivalent compounds as potential neuroprotectants for Alzheimer’s disease: Impact of the spacer on biological activity

“…13 This is in agreement with our recent studies to show that the spacer composition is a key factor in optimizing protective potency. 28 This also suggests that incorporation of a piperazine moiety into the spacer represents a means to improve potency for future structural modifications. Overall, the increase of spacer length from 21 to 37 atoms did not significantly change the protective potency (Table 1).…”

Development of bivalent compounds as potential neuroprotectants for Alzheimer’s disease

“…10 Among the tested bivalent compounds, 21MO shows the most potent protection with an EC 50 of 81.86 nM. When compared to a similar bivalent compound with a spacer length of 21 atoms yet different composition, 11 the protective potency is increased by 23 fold (81.86 vs 1848.66 nM, respectively). This further demonstrated that incorporation of a piperazine ring into the spacer significantly improves potency and spacer composition is important for the molecular design of such bivalent compounds.…”