Diketo-Ketoenol Tautomers in Curcuminoids: Synthesis, Separation of Tautomers, and Kinetic and Structural Studies.

Curcumin and its congeners exist in an equilibrium between diketo and ketoenol tautomers, which have different potencies to bind biomolecules. This work describes procedures for the preparation of 4-alkylated curcumin derivatives and the separation of their two tautomeric forms. Comprehensive NMR studies of the tautomer equilibria in various solvents have been accomplished. Additionally, a pure ketoenol tautomeric form of the active pharmaceutical ingredient (API) ASC-JM17 has been unequivocally determined by X-ray crystallography. Two different polymorphs of this API have been microscopically identified in the X-ray sample and manually separated, and a solid-state NMR study of the two polymorphs has also been performed. This work reports on the slow kinetics of diketo-ketoenol tautomerization in particular solvents that allow the separation and full characterization of both curcuminoids' tautomers.

Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors.

The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3',4'-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.

Enantioselective PCCP Brønsted acid-catalyzed aminalization of aldehydes.

Here we present an enantioselective aminalization of aldehydes catalyzed by Brønsted acids based on pentacarboxycyclopentadienes (PCCPs). The cyclization reaction using readily available anthranilamides as building blocks provides access to valuable 2,3-dihydroquinazolinones containing one stereogenic carbon center with good enantioselectivity (ee up to 80%) and excellent yields (up to 97%).