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 transformati...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.展开更多
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...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.展开更多
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 m...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.展开更多
An organocatalytic asymmetric [3+2] cycloaddition of trifluoromethyl-containing azomethine ylides with cyclic 2,4-dienones was developed.The process enables efficient incorporation of CF3 groups into functionalized sp...An organocatalytic asymmetric [3+2] cycloaddition of trifluoromethyl-containing azomethine ylides with cyclic 2,4-dienones was developed.The process enables efficient incorporation of CF3 groups into functionalized spiro [pyrro lid in-3,2'-oxindoles] in high yields with good to excellent enantio-and diastereoselectivities.展开更多
基金We gratefully acknowledge the Provincial Planning Project of the Zhejiang Provincial Science and Technology Department(No.LGF19B060005)for financial support.
文摘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.
基金supported by the National Key R&D Program of China(Grant No.2020YFA0509100)the National Natural Science Foundation of China(Grants 21738002,82030105,81725020 and 81903436)。
文摘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.
基金supported by the National Natural Science Foundation of China(no.22031008)the Science Foundation of Wuhan(no.2020010601012192).
文摘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.
基金supported by the National Natural Science Foundation of China(Nos.21272068,21572056,21801077)China Postdoctoral Science Foundation(Nos.2017M621382,2018T110355)+1 种基金Shanghai Sailing Program(No.18YF1406200)the Fundamental Research Funds for the Central Universities。
文摘An organocatalytic asymmetric [3+2] cycloaddition of trifluoromethyl-containing azomethine ylides with cyclic 2,4-dienones was developed.The process enables efficient incorporation of CF3 groups into functionalized spiro [pyrro lid in-3,2'-oxindoles] in high yields with good to excellent enantio-and diastereoselectivities.
