Chiral aryl cyclohex-3-en ether scaffold is widely present in bioactive natural products and drugs.The exploitation of efficient and enantioselective methods for the construction of aryl cyclohex-3-en ether scaffold i...Chiral aryl cyclohex-3-en ether scaffold is widely present in bioactive natural products and drugs.The exploitation of efficient and enantioselective methods for the construction of aryl cyclohex-3-en ether scaffold is significant.Herein we disclose a chiral N,N’-dioxide/Lewis acid complex-catalyzed asymmetric inverse-electron-demand Diels-Alder(IEDDA)reaction using electron-deficient 3-carboalkoxyl-2-pyrones and less electron-enriched aryl enol ethers as reactants.A wide range of non-and 1,2-disubstituted acyclic aryl enol ethers are applicable to deliver diverse chiral bridged bicyclic lactones in high yields and stereoselectivities(up to 96%yield,>20:1 dr,97:3 er).The bridged bicyclic lactone core can be easily converted into chiral aryl cyclohex-3-en ether scaffold.Notably,DFT calculations revealed a stepwise and endo mechanism to explain the high enantioselectivity controlled by the cooperative effect of the steric factors and the dispersion interactions between ligands and enol ethers.展开更多
The absorption of peptides and proteins delivered orally is minimum because of the intestine epithelial barrier.There are few known active transport mechanisms for macromolecules including the neonatal Fc Receptor(FcR...The absorption of peptides and proteins delivered orally is minimum because of the intestine epithelial barrier.There are few known active transport mechanisms for macromolecules including the neonatal Fc Receptor(FcRn)for the absorption and secretion of IgGs in infant and adult intestine.We had previously described the FnAb-8 protein that could bind to h FcRn tightly at pH 6.0 but barely at pH 7.4.In this study,we examined its uptake,biodistribution and pharmacokinetics after peroral administration in both wild-type and human FcRn transgenic(Tg)mice.FnAb-8 was modified to contain trans-cyclooctene(TCO)which could interact with18 F labeled tetrazine in situ via the bioorthogonal inverseelectron-demand Diels-Alder reaction.We showed that FnAb-8 had a tendency to distribute and persist in the Tg mice intestine for an extended duration of time.It could also be absorbed into the circulation and distributed systemically over a long period of time up to 172 h.The improvement in oral uptake and concentration in the intestine tissue may be valuable for designing oral delivery of biopharmaceuticals,especially for diseases involving the gastric intestinal tissue.展开更多
Current antibody–drug conjugates(ADCs)suffer from low tissue penetration and significant side effects,largely due to the permanent linkage and/or premature release of cytotoxic payloads.Herein,we developed a prodrug...Current antibody–drug conjugates(ADCs)suffer from low tissue penetration and significant side effects,largely due to the permanent linkage and/or premature release of cytotoxic payloads.Herein,we developed a prodrug–antibody conjugate(ProADC)strategy by conjugating a bioorthogonal-activatable prodrug with an antibody that allowed on-target release and on-demand activation of cytotoxic drugs at a tumor site.The bioorthogonal-caged prodrug exhibited an enhanced permeability into and on-demand activation within cancer cells,while the pH-sensitive ADC linker allowed on-target release of the anticancer agent.Together,the ProADCs showed enhanced tumor penetration and alleviated side effects for use as an on-target and on-demand chemotherapy agents.展开更多
基金National Natural Science Foundation of China(Nos.22001177,22203023)Guangdong Pearl River Talent Program(no.2021QN020268)+3 种基金the Natural Science Foundation of Guangdong Province(Nos.2024A1515012381,2022A1515011859)Shenzhen Bay Laboratory Startup Fund(No.S201100003)Major Program of Shenzhen Bay Laboratory(No.S211101001-4)Shenzhen Bay Qihang Fellow Program(No.QH23001)for generous financial support.
文摘Chiral aryl cyclohex-3-en ether scaffold is widely present in bioactive natural products and drugs.The exploitation of efficient and enantioselective methods for the construction of aryl cyclohex-3-en ether scaffold is significant.Herein we disclose a chiral N,N’-dioxide/Lewis acid complex-catalyzed asymmetric inverse-electron-demand Diels-Alder(IEDDA)reaction using electron-deficient 3-carboalkoxyl-2-pyrones and less electron-enriched aryl enol ethers as reactants.A wide range of non-and 1,2-disubstituted acyclic aryl enol ethers are applicable to deliver diverse chiral bridged bicyclic lactones in high yields and stereoselectivities(up to 96%yield,>20:1 dr,97:3 er).The bridged bicyclic lactone core can be easily converted into chiral aryl cyclohex-3-en ether scaffold.Notably,DFT calculations revealed a stepwise and endo mechanism to explain the high enantioselectivity controlled by the cooperative effect of the steric factors and the dispersion interactions between ligands and enol ethers.
基金funded by the Natural Science Foundation of China(Grant no.81690262)。
文摘The absorption of peptides and proteins delivered orally is minimum because of the intestine epithelial barrier.There are few known active transport mechanisms for macromolecules including the neonatal Fc Receptor(FcRn)for the absorption and secretion of IgGs in infant and adult intestine.We had previously described the FnAb-8 protein that could bind to h FcRn tightly at pH 6.0 but barely at pH 7.4.In this study,we examined its uptake,biodistribution and pharmacokinetics after peroral administration in both wild-type and human FcRn transgenic(Tg)mice.FnAb-8 was modified to contain trans-cyclooctene(TCO)which could interact with18 F labeled tetrazine in situ via the bioorthogonal inverseelectron-demand Diels-Alder reaction.We showed that FnAb-8 had a tendency to distribute and persist in the Tg mice intestine for an extended duration of time.It could also be absorbed into the circulation and distributed systemically over a long period of time up to 172 h.The improvement in oral uptake and concentration in the intestine tissue may be valuable for designing oral delivery of biopharmaceuticals,especially for diseases involving the gastric intestinal tissue.
文摘Current antibody–drug conjugates(ADCs)suffer from low tissue penetration and significant side effects,largely due to the permanent linkage and/or premature release of cytotoxic payloads.Herein,we developed a prodrug–antibody conjugate(ProADC)strategy by conjugating a bioorthogonal-activatable prodrug with an antibody that allowed on-target release and on-demand activation of cytotoxic drugs at a tumor site.The bioorthogonal-caged prodrug exhibited an enhanced permeability into and on-demand activation within cancer cells,while the pH-sensitive ADC linker allowed on-target release of the anticancer agent.Together,the ProADCs showed enhanced tumor penetration and alleviated side effects for use as an on-target and on-demand chemotherapy agents.
