PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibi...PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.展开更多
为明确the new Pad、iPhone4s是否具备专业显示设备的显示性能,以液晶专业显示器A为参考,对这3个显示设备的时间稳定性、不同亮度下不同颜色显示的空间均匀性、不同亮度下色域覆盖率、色品恒定性、通道相加性、设备色域6个方面的性能进...为明确the new Pad、iPhone4s是否具备专业显示设备的显示性能,以液晶专业显示器A为参考,对这3个显示设备的时间稳定性、不同亮度下不同颜色显示的空间均匀性、不同亮度下色域覆盖率、色品恒定性、通道相加性、设备色域6个方面的性能进行了测试。实验结果表明:iPhone4s在时间稳定性、颜色显示的空间均匀性以及色域覆盖率的稳定性方面优于the new Pad;the new Pad在通道可加性、色品恒定性方面优于iPhone4s;3个显示设备中the new Pad的色域覆盖率最大,iPhone4s的最小;the new Pad各项性能与专业显示器A的相近。The new Pad基本达到专业显示设备的显示性能要求,可作为专业显示设备的辅助设备使用,iPhone4s没有达到专业显示设备的显示性能要求,不适合作为专业显示设备的辅助设备使用。展开更多
Plant intracellular nucleotide-binding leucine-rich repeat(NLR)receptors with an N-terminal Toll/Interleukin-1 recep-tor(TIR)domain detect pathogen effectors to produce TIR-catalyzed signaling molecules for activation...Plant intracellular nucleotide-binding leucine-rich repeat(NLR)receptors with an N-terminal Toll/Interleukin-1 recep-tor(TIR)domain detect pathogen effectors to produce TIR-catalyzed signaling molecules for activation of plant immunity.Plant immune signaling by TIR-containing NLR(TNL)proteins converges on Enhanced Disease Suscepti-bility 1(EDS1)and its direct partners Phytoalexin Deficient 4(PAD4)or Senescence-Associated Gene 101(SAG101).TNL signaling also require helper NLRs N requirement gene 1(NRG1)and activated disease resistance 1(ADR1).In two recent remarkable papers published in Science,the authors show that the TIR-containing proteins catalyze and produce two types of signaling molecules,ADPr-ATP/diADPR and pRib-AMP/ADP.Importantly,they demonstrate that EDS1-SAG101 and EDS1-PAD4 modules are the receptor complexes for ADPr-ATP/diADPRp and Rib-AMP/ADP,respec-tively,which allosterically promote EDS1-SAG101 interaction with NRG1 and EDS1-PAD4 interaction with ADR1.Thus,two different small molecules catalyzed by TIR-containing proteins selectively activate the downstream two distinct branches of EDS1-mediated immune signalings.These breakthrough studies significantly advance our understanding of TNL downstream signaling pathway.展开更多
基金supported by the National Natural Science Foundation of China(21502098,21672105,21725204,91753124)Natural Science Foundation of Tianjin(17JCYBJC19700,18JCZDJC32800)+1 种基金Qingdao National Laboratory for Marine Science and Technologythe State Key Laboratory of Elemento-Organic Chemistry at Nankai University
文摘PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.
文摘为明确the new Pad、iPhone4s是否具备专业显示设备的显示性能,以液晶专业显示器A为参考,对这3个显示设备的时间稳定性、不同亮度下不同颜色显示的空间均匀性、不同亮度下色域覆盖率、色品恒定性、通道相加性、设备色域6个方面的性能进行了测试。实验结果表明:iPhone4s在时间稳定性、颜色显示的空间均匀性以及色域覆盖率的稳定性方面优于the new Pad;the new Pad在通道可加性、色品恒定性方面优于iPhone4s;3个显示设备中the new Pad的色域覆盖率最大,iPhone4s的最小;the new Pad各项性能与专业显示器A的相近。The new Pad基本达到专业显示设备的显示性能要求,可作为专业显示设备的辅助设备使用,iPhone4s没有达到专业显示设备的显示性能要求,不适合作为专业显示设备的辅助设备使用。
基金support from the National Natural Science Foundation of China(31925032 and 31870143).
文摘Plant intracellular nucleotide-binding leucine-rich repeat(NLR)receptors with an N-terminal Toll/Interleukin-1 recep-tor(TIR)domain detect pathogen effectors to produce TIR-catalyzed signaling molecules for activation of plant immunity.Plant immune signaling by TIR-containing NLR(TNL)proteins converges on Enhanced Disease Suscepti-bility 1(EDS1)and its direct partners Phytoalexin Deficient 4(PAD4)or Senescence-Associated Gene 101(SAG101).TNL signaling also require helper NLRs N requirement gene 1(NRG1)and activated disease resistance 1(ADR1).In two recent remarkable papers published in Science,the authors show that the TIR-containing proteins catalyze and produce two types of signaling molecules,ADPr-ATP/diADPR and pRib-AMP/ADP.Importantly,they demonstrate that EDS1-SAG101 and EDS1-PAD4 modules are the receptor complexes for ADPr-ATP/diADPRp and Rib-AMP/ADP,respec-tively,which allosterically promote EDS1-SAG101 interaction with NRG1 and EDS1-PAD4 interaction with ADR1.Thus,two different small molecules catalyzed by TIR-containing proteins selectively activate the downstream two distinct branches of EDS1-mediated immune signalings.These breakthrough studies significantly advance our understanding of TNL downstream signaling pathway.
