A Chemical Analog of Curcumin as an Improved Inhibitor of Amyloid Abeta Oligomerization

Abstract

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin.

Effect of curcumin analogs onα-synuclein aggregation and cytotoxicity

“…Recently Orlando et al, have screened and analyzed a library of artificial curcumin analogs that inhibited Aβ oligomerization either equal to or more than the effect of curcumin28. We selected nine analogs of curcumin such that they are structurally similar to curcumin, but have different functional group and could have potential effect on α-Syn aggregation.…”

Protein Folding and Aggregation into Amyloid: The Interference by Natural Phenolic Compounds

“…These ideas on the importance of the Cur structural features have been validated by solid state NMR experiments, showing that in Cur, the methoxy and hydroxyl groups adjacent to the aromatic carbons are involved in the Cur-Aβ interaction [200]. These data were confirmed by a study carried out with several Cur synthetic analogs, further suggesting that the carbon spacer between the two aryl rings must contain an enone group to ensure the anti-amyloidogenic activity [201]. The integration of these results with those obtained by Reinke et al [202] by using another library of Cur analogs and the Aβ42 peptide led to hypothesize that a fairly rigid unsaturated, 8–16 Ǻ-long, carbon chain provides the best linker to accommodate the aromatic rings in two distinct (yet unidentified) binding sites on the target peptide.…”

Curcumin and its Derivatives: Their Application in Neuropharmacology and Neuroscience in the 21st Century

“…chemically synthesized curcumin analogs with several modifications on the basic structure of the curcumin [257]. Several structural features had been identified contributing to anti-aggregation of A β .…”