This study presents an efficient and innovative allylation strategy utilizing C/N/O nucleophilic reagents with attenuated reactivity,enabling the construction of versatile allyl compounds.The approach focuses on the s...This study presents an efficient and innovative allylation strategy utilizing C/N/O nucleophilic reagents with attenuated reactivity,enabling the construction of versatile allyl compounds.The approach focuses on the sequential allylation of dihalides in large-scale chemical manufacturing,effectively addressing the challenge of achieving selectivity in cascade reactions.The methodology is centered on the Cu-catalyzed C-olefination of alkynes with dihalides,significantly expediting the synthesis of a diverse array of finely conjugated enyne derivatives.Furthermore,a base-facilitated sequential condensation process has been developed to achieve the N-allylation of hydrazines,yielding a wide range of trisubstituted alkenyl hydrazones.Additionally,the protocol enables the synthesis of high-value ester compounds through O-allylation or esterification with dihalides.This transformation also facilitates the one-step synthesis of a variety of essential pharmaceuticals,demonstrating its broad synthetic utility and potential.展开更多
As confusion mounts over RNA isoforms involved in phenotypic plasticity,aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity(ITH).Prot...As confusion mounts over RNA isoforms involved in phenotypic plasticity,aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity(ITH).Protease serine 3(PRSS3),possessing four splice variants(PRSS3-SVs;PRSS3-V1—V4),is an indispensable trypsin that shows paradoxical effects on cancer development.Here,we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer,exhibiting opposing functions and clinical outcomes,namely,oncogenic PRSS3-V1 and PRSS3-V2 versus tumorsuppressive PRSS3-V3,by targeting different downstream genes.We identified an intragenic CpG island(iCpGI)in PRSS3.Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1(MZF1)to regulate PRSS3 transcription.The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression.Epigenetic silencing of PRSS3-V3 via i CpGI methylation(iCpGIm)in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease.Thus,UHRF1/DNMT1—MZF1 axismodulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs,conferring nongenetic functional ITH,with implications for early detection of lung cancer and targeted therapies.展开更多
基金grateful to the Hundred-Talent Program of the Chinese Academy of Sciences(YBR2025002)the Key project of International Cooperation Bureau,CAS(040GJHZ2024013MI)+1 种基金the Natural Science Foundation of Shanxi Province of China(202303021221256)the Research Project Supported by Shanxi Scholarship Council of China and the State Key Laboratory of Coal Conversion,Institute of Coal Chemistry,CAS(2024KJT003).
文摘This study presents an efficient and innovative allylation strategy utilizing C/N/O nucleophilic reagents with attenuated reactivity,enabling the construction of versatile allyl compounds.The approach focuses on the sequential allylation of dihalides in large-scale chemical manufacturing,effectively addressing the challenge of achieving selectivity in cascade reactions.The methodology is centered on the Cu-catalyzed C-olefination of alkynes with dihalides,significantly expediting the synthesis of a diverse array of finely conjugated enyne derivatives.Furthermore,a base-facilitated sequential condensation process has been developed to achieve the N-allylation of hydrazines,yielding a wide range of trisubstituted alkenyl hydrazones.Additionally,the protocol enables the synthesis of high-value ester compounds through O-allylation or esterification with dihalides.This transformation also facilitates the one-step synthesis of a variety of essential pharmaceuticals,demonstrating its broad synthetic utility and potential.
基金National Natural Science Foundation of China(NSFC grant No.32200462,China)National Natural Science Foundation of China(NSFC grant No.81872021,China)+4 种基金Beijing Municipal Administration of Hospitals Youth Program(grant No.QMS20221603,China)R&D Program of Beijing Municipal Education Commission(grant No.KM202110025004,China)Beijing Natural Science Foundation of China(BJSFC No.7214242,China)Beijing Municipal Administration of Hospitals Incubating Program(grant No.PX2021063,China)Intramural Research Funding Program from Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital。
文摘As confusion mounts over RNA isoforms involved in phenotypic plasticity,aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity(ITH).Protease serine 3(PRSS3),possessing four splice variants(PRSS3-SVs;PRSS3-V1—V4),is an indispensable trypsin that shows paradoxical effects on cancer development.Here,we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer,exhibiting opposing functions and clinical outcomes,namely,oncogenic PRSS3-V1 and PRSS3-V2 versus tumorsuppressive PRSS3-V3,by targeting different downstream genes.We identified an intragenic CpG island(iCpGI)in PRSS3.Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1(MZF1)to regulate PRSS3 transcription.The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression.Epigenetic silencing of PRSS3-V3 via i CpGI methylation(iCpGIm)in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease.Thus,UHRF1/DNMT1—MZF1 axismodulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs,conferring nongenetic functional ITH,with implications for early detection of lung cancer and targeted therapies.
