Nitroxyl Hybrids with Curcumin and Stilbene Scaffolds Display
\nPotent Antioxidant Activity, Remodel the Amyloid Beta
\nOligomer, and Reverse Amyloid Beta-Induced Cytotoxicity

The disorder and heterogeneity of low-molecular-weight amyloid-beta oligomers (AβOs) underlie their participation in multiple modes of cellular dysfunction associated with the etiology of Alzheimer’s disease (AD). The lack of specifed conformational states in these species complicates
\nefforts to select or design small molecules to targeting discrete pathogenic states. Furthermore, targeting AβOs alone may be therapeutically insuffcient, as AD progresses as a multifactorial, self-amplifying cascade. To address these challenges, we have screened the activity of seven new
\ncandidates that serve as Paramagnetic Amyloid Ligand (PAL) candidates. PALs are bifunctional small
\nmolecules that both remodel the AβO structure and localize a potent antioxidant that mimics the
\nactivity of SOD within live cells. The candidates are built from either a stilbene or curcumin scaffold
\nwith nitroxyl moiety to serve as catalytic antioxidants. Measurements of PAL AβO binding and
\nremolding along with assessments of bioactivity allow for the extraction of useful SAR information
\nfrom screening data. One candidate (HO-4450; PMT-307), with a six-membered nitroxyl ring attached to a stilbene ring, displays the highest potency in protecting against cell-derived Aβ. A preliminary low-dose evaluation in AD model mice provides evidence of modest treatment effects by HO-4450. The results for the curcumin PALs demonstrate that the retention of the native curcumin phenolic groups is advantageous to the design of the hybrid PAL candidates. Finally, the PAL remodeling of AβO secondary structures shows a reasonable correlation between a candidate’s bioactivity and its ability to reduce the fraction of antiparallel β-strand.