Electrochemical synthesis of 3-halogenated spiro [4,5]trienones based on dearomative spirocyclization strategy

A novel and green route have been developed for the electrochemical synthesis of 3-halogenated spiro[4.5]trienones based on dearomative spirocyclization of alkynes with NaX(Br,I)as the halogen source.This transformation was performed in an undivided cell under mild conditions.A wide range of substituted 3-halogenated spiro[4.5]trienones products was prepared in moderate-to-good yields,showing a broad scope and functional group tolerance.In addition,this approach was further extended to access fused tricyclic 6,7-dihydro-3H-pyrrolo[2,1-j]quinoline-3,9(5H)-diones.

Electrochemical Oxidation Dearomatization of Anisol Derivatives toward Spiropyrrolidines and Spirolactones

Spiro compounds are widely prevalent in biological activities and natural products.However,developing new strategies for their efficient synthesis and derivatization remains a challenge.Outstanding progress has been made in the synthesis of spiro compounds through dearomatization of aromatic compounds,most of them are mediated by the hypervalent iodine reagents.Herein,we report a method of anodic oxidation spiroamination and spirolactonization of anisole derivatives with concomitant cathodic reduction of protons in the absence of hypervalent iodine reagents.A wide variety of spiropyrrolidines and spirolactones with diverse functional groups made useful scaffolds in this transformation,with yields up to 97%.Moreover,hectogram-scale synthesis could supply target product with 83% yield in a flow electrochemical cell using carbon paper as the anode and nickel plate as the cathode,demonstrating the potential application of this method.

Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36 l(KD= 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX) models. It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.