Paullones constitute a new family of benzazepinones with promising antitumoral properties. They were recently described as potent, ATP‐competitive, inhibitors of the cell cycle regulating cyclin‐dependent kinases (CDKs). We here report that paullones also act as very potent inhibitors of glycogen synthase kinase‐3β (GSK‐3β) (IC₅₀: 4–80 nm) and the neuronal CDK5/p25 (IC₅₀: 20–200 nm). These two enzymes are responsible for most of the hyperphosphorylation of the microtubule‐binding protein tau, a feature observed in the brains of patients with Alzheimer’s disease and other neurodegenerative ‘taupathies’. Alsterpaullone, the most active paullone, was demonstrated to act by competing with ATP for binding to GSK‐3β. Alsterpaullone inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK‐3β in Alzheimer’s disease. Alsterpaullone also inhibits the CDK5/p25‐dependent phosphorylation of DARPP‐32 in mouse striatum slices in vitro. This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders.

Biocatalytic alkylations are important reactions to obtain chemo‐, regio‐ and stereoselectively alkylated compounds. This can be achieved using S‐adenosyl‐l‐methionine (SAM)‐dependent methyltransferases and SAM analogs. It was recently shown that a halide methyltransferase (HMT) from Chloracidobacterium thermophilum can synthesize SAM from SAH and methyl iodide. We developed an iodide‐based assay for the directed evolution of an HMT from Arabidopsis thaliana and used it to identify a V140T variant that can also accept ethyl‐, propyl‐, and allyl iodide to produce the corresponding SAM analogs (90, 50, and 70 % conversion of 15 mg SAH). The V140T AtHMT was used in one‐pot cascades with O‐methyltransferases (IeOMT or COMT) to achieve the regioselective ethylation of luteolin and allylation of 3,4‐dihydroxybenzaldehyde. While a cascade for the propylation of 3,4‐dihydroxybenzaldehyde gave low conversion, the propyl‐SAH intermediate could be confirmed by NMR spectroscopy.