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The intramolecular Diels-Alder reaction (IMDA) of a butenolide derivative, as an entry to the type II abyssomicin scaffold, and the total synthesis of (±)-abyssomicin 2 and (±)-neoabyssomicin B are reported for the first time. A facile route to the IMDA precursor, the formation of a type I intermediate and two paths to (±)-neoabyssomicin B are also discussed.

Background: Alzheimer’s disease (AD) involves impairment of Aβ clearance. Neprilysin (NEP) is the most efficient Aβ peptidase. Enhancement of the activity or expression of NEP may provide a prominent therapeutic strategy against AD. Aims: Ten hydroxylated monocarbonyl curcumin derivatives were designed, synthesized and evaluated for their NEP upregulating potential using sensitive fluorescence-based Aβ digestion and inhibition assays. Results: Compound 4 was the most active one, resulting in a 50% increase in Aβ cleavage activity. Cyclohexanone-bearing derivatives exhibited higher activity enhancement compared to their acetone counterparts. Inhibition experiments with the NEP-specific inhibitor thiorphan resulted in dramatic cleavage reduction. Conclusion: The increased Aβ cleavage activity and the ease of synthesis of 4 renders it an extremely attractive lead compound.

Three novel pyrazolo[3,4-b]pyridines were synthesized via the cyclization of 5-amino-1-phenylpyrazole with the corresponding unsaturated ketone in the catalytic presence of ZrCl4. The ketones were afforded by modifying a stabilized ylide facilitated Wittig reaction in fairly high yields. The novel compounds exhibited exciting photophysical properties with the dimethylamine phenyl-bearing pyrazolopyridine showing exceptionally large Stoke’s shifts. Finally, both the dimethylamino- and the pyrene-substituted compounds demonstrated high and selective binding to amyloid plaques of Alzheimer’s disease (AD) patient brain slices upon fluorescent confocal microscopy observation. These results reveal the potential application of pyrazolo[3,4-b]pyridines in the development of AD amyloid plaque probes of various modalities for AD diagnosis.