The total synthesis of berberine and selected analogues, and their evaluation as amyloid beta aggregation inhibitors.

The total synthesis of berberine and selected analogues. And their evaluation as amyloid ß (Aß) aggregation inhibitors is described. The key step in the synthesis, the assembly of the berberine framework, was accomplished using an intermolecular Heck reaction. Berberine analog 17 incorporating a tertiary amine moiety showed good anti Aß aggregation activity, water solubility, and almost no toxicity to nerve cells.

Design, synthesis and evaluation of diaryl γ-dihydropyrone derivatives as cyclocurcumin mimetics and inhibitors of the aggregation of amyloid ß.

A structure activity relationship study of cyclocurcumin-derived, diaryl γ-dihydropyrone-based inhibitors of amyloid ß aggregation is described. Optimization of the diaryl γ-dihydropyrone framework and two phenolic rings resulted in the identification of diaryl γ-dihydropyrone type cyclocurcumin analogue AY1511, which exhibited potent anti-amyloid ß aggregation activity (leading to nanorod-like fragments), sufficient water solubility, and low cytotoxicity.

Anti-Alzheimer's flavanolignans from Ceiba pentandra aerial parts.

Four flavanolignans, ceibapentains A (1) and B (2) and cinchonains Ia (3) and Ib (4), were isolated for the first time from an ethyl acetate extract of Ceiba pentandra (L) (Bombacaceae) aerial parts. The ceibapentains A (1) and B (2) are new compounds and their structures, including the absolute configurations, were determined by HRESIMS, 1D and 2D NMR, and electronic circular dichroism analyses, then compared with reported data. Compounds 1-4 were tested for their anti-Alzheimer's activity via an assessment of their inhibitory effect on amyloid ß42 aggregation using a thioflavin T assay. The results revealed that cinchonain Ia (3) showed a higher inhibitory effect (91%) than the standard curcumin (70%). Compounds 1, 2, and 4 exhibited moderate activity, with inhibition ratios of 43%, 47%, and 58%, respectively. A molecular docking study on the binding mode of 3 and curcumin with an amyloid ß1-40 peptide fibril structure indicated a high affinity of cinchonain 1a (3) towards amyloid ß1-40 peptide, in agreement with the experimental results.

Design, synthesis, and evaluation of a water soluble C5-monoketone type curcumin analogue as a potent amyloid ß aggregation inhibitor.

A structure activity relationship study of curcumin analogues for the inhibition of amyloid ß aggregation is described. Optimization of the o-phenol and olefin spacer resulted in the identification of the C5-monoketone type curcumin analogue AY1319, which exhibited potent anti-amyloid ß aggregation activity (leading to nanorod-like fragments), sufficient water solubility, and low cytotoxicity.

Design, synthesis and evaluation of curcumin-based fluorescent probes to detect Aß fibrils.

Amyloid ß fibrillation is an early event in Alzheimer's disease, so its detection is important to understand its roles in Alzheimer's disease. Curcumin, which has poor water solubility, has been reported to have many pharmacological activities including potent anti-amyloid ß fibril activity in Alzheimer's disease. In this study, we found that curcumin analogues with the fluorescence property instead of non-inhibition of amyloid ß fibrils. The development of new curcumin analogue, Me-CUR (9), as fluorescent switchable probe to detect amyloid ß fibrils is described. Me-CUR (9) shows excellent fluorescence, especially higher than ThT (4), in the presence of amyloid ß fibrils. These results suggest that Me-CUR (9) can become a useful in vitro amyloid fluorescence sensor for diagnosis of Alzheimer's disease.