Chemotherapeutic paclitaxel(PTX) formulations are widely used in clinical cancer treatment;however, they are also associated with concomitant programmed death-ligand(PD-L1) upregulation and an immunosuppressive microe...Chemotherapeutic paclitaxel(PTX) formulations are widely used in clinical cancer treatment;however, they are also associated with concomitant programmed death-ligand(PD-L1) upregulation and an immunosuppressive microenvironment. Herein, we rationally designed carrier-free, reduction-sensitive PTX dimer self-assembling nanoprodrugs(di PC NPs), composed of a glutathione(GSH)-responsive PTX dimer prodrug(di PTX) and the PD-L1 downregulator celastrol(Cel) for combinational chemoimmunotherapy. Following intravenous administration, the di PC NPs exhibited prolonged blood circulation and preferential tumor accumulation by exploiting the enhanced permeability and retention effect. Subsequently, the elevated GSH levels in tumor cells cleaved the disulfide bonds,triggering the rapid release of PTX and Cel. The released PTX elicited potent cytotoxic effects and induced immunogenic cell death(ICD), whereas the released Cel synergistically enhanced ICD and downregulated PD-L1 expression in tumor cells. Together, these effects resulted in remarkable antitumor efficacy with exhibited a favorable safety profile within the therapeutic window in both Lewis lung carcinoma cells and B16F10 tumorbearing mice. Our findings highlight a promising strategy for highly efficient combination chemoimmunotherapy.展开更多
Comprehensive Summary.Herein, an intermolecular palladium(II)-catalyzed regioselective [4+2] benzannulation reaction capable of converting 2-pyridones into quinolinones was developed using electron-deficient alkenes a...Comprehensive Summary.Herein, an intermolecular palladium(II)-catalyzed regioselective [4+2] benzannulation reaction capable of converting 2-pyridones into quinolinones was developed using electron-deficient alkenes as two-carbon units. An examination of the reaction mechanism indicated that the extension from 2-pyridone to quinolinone was likely facilitated through a series of sequential C—H activation reactions or 6π electrocyclization, culminating in dehydrogenative aromatization. This method of diversity-oriented synthesis of quinolinone derivatives is characterized by a broad substrate scope, atom economy, and excellent chemical selectivity. In addition, these quinolinone derivatives exhibit fluorescent absorption within the visible-light spectrum, which makes them suitable candidates for the development of innovative fluorescent probes.展开更多
Herein,we report an asymmetric two-component alkenyl Catellani reaction for the construction of C—N axial chirality through a palladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer...Herein,we report an asymmetric two-component alkenyl Catellani reaction for the construction of C—N axial chirality through a palladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer process.Various partially aromatic iodinated 2-pyridones,quinolones,coumarin and uracil substrates react with 2,6-disubstituted aryl bromides with a tethered amide group,to afford a wide variety of polycyclic C—N atropisomers(38 examples,up to 97%e.e.).The obtained C—N axial chirality originates from the preformed transient C—C axial chirality with high fidelity.The synthetic utility of this chemistry is demonstrated by facile prepa-ration of complex quinoline and pyridine based C—N atropisomers through a N-deprotection and aromatization sequence.In addi-tion,a remote axial-to-central diastereoinduction process dictated by C—N axial chirality is observed with excellent diastereocontrol.展开更多
基金the National Natural Science Foundation of China (No. 82374301)the State Key Laboratory of Southwestern Chinese Medicine Resources (No. SKLTCM202410)+2 种基金the Key Project of Anhui Province Department of Education (No. 2023AH030070, 2024AH051040)Anhui Province Key Laboratory, China (KFKT202305, KFKT202507, 2024ZYFBAHKLA11, and 2024ZYFBAHKLA15)Greater Health Research Institute of Hefei Comprehensive National Science Center, China (2023CXMMTCM005)。
文摘Chemotherapeutic paclitaxel(PTX) formulations are widely used in clinical cancer treatment;however, they are also associated with concomitant programmed death-ligand(PD-L1) upregulation and an immunosuppressive microenvironment. Herein, we rationally designed carrier-free, reduction-sensitive PTX dimer self-assembling nanoprodrugs(di PC NPs), composed of a glutathione(GSH)-responsive PTX dimer prodrug(di PTX) and the PD-L1 downregulator celastrol(Cel) for combinational chemoimmunotherapy. Following intravenous administration, the di PC NPs exhibited prolonged blood circulation and preferential tumor accumulation by exploiting the enhanced permeability and retention effect. Subsequently, the elevated GSH levels in tumor cells cleaved the disulfide bonds,triggering the rapid release of PTX and Cel. The released PTX elicited potent cytotoxic effects and induced immunogenic cell death(ICD), whereas the released Cel synergistically enhanced ICD and downregulated PD-L1 expression in tumor cells. Together, these effects resulted in remarkable antitumor efficacy with exhibited a favorable safety profile within the therapeutic window in both Lewis lung carcinoma cells and B16F10 tumorbearing mice. Our findings highlight a promising strategy for highly efficient combination chemoimmunotherapy.
基金the Natural Science Foundation of Anhui University of Chinese Medicine(2021rczd003 and 2022AH050440)the Cooperation Project of Fuyang Municipal Government and Fuyang Normal University(No.SXHZ202002)+1 种基金the Natural Science Foundation of Fuyang Normal University(FYKFKT24001)the National Natural Science Foundation of China(Grant No.22301074)for financial support.
文摘Comprehensive Summary.Herein, an intermolecular palladium(II)-catalyzed regioselective [4+2] benzannulation reaction capable of converting 2-pyridones into quinolinones was developed using electron-deficient alkenes as two-carbon units. An examination of the reaction mechanism indicated that the extension from 2-pyridone to quinolinone was likely facilitated through a series of sequential C—H activation reactions or 6π electrocyclization, culminating in dehydrogenative aromatization. This method of diversity-oriented synthesis of quinolinone derivatives is characterized by a broad substrate scope, atom economy, and excellent chemical selectivity. In addition, these quinolinone derivatives exhibit fluorescent absorption within the visible-light spectrum, which makes them suitable candidates for the development of innovative fluorescent probes.
文摘Herein,we report an asymmetric two-component alkenyl Catellani reaction for the construction of C—N axial chirality through a palladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer process.Various partially aromatic iodinated 2-pyridones,quinolones,coumarin and uracil substrates react with 2,6-disubstituted aryl bromides with a tethered amide group,to afford a wide variety of polycyclic C—N atropisomers(38 examples,up to 97%e.e.).The obtained C—N axial chirality originates from the preformed transient C—C axial chirality with high fidelity.The synthetic utility of this chemistry is demonstrated by facile prepa-ration of complex quinoline and pyridine based C—N atropisomers through a N-deprotection and aromatization sequence.In addi-tion,a remote axial-to-central diastereoinduction process dictated by C—N axial chirality is observed with excellent diastereocontrol.
