A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A (1), possessing a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps via a visible light mediated late‐stage Schenck ene reaction of (‐)‐1α,6α‐diacetoxyjungermannenone C (2). Along the way, a striking UV light induced bicyclo[3.2.1]octene ring rearrangement was applied to afford (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one (4). The photoinduced divergent skeletal rearrangements strongly suggest a possible biogenetic relationship between 1, 2 and 4
We report the total synthesis of (±)-antroquinonol based on a concise and efficient route. Key features include two different strategies to install the required three contiguous stereogenic centers, which not only furnish the desired natural product but also provide natural product congeners for further biological studies.
Chen, K., Lei, X.
Current Opinion in Green and Sustainable Chemistry 2018, 11, 9–14
We have witnessed the striking advancement of C–H functionalization in organic synthesis over the past decade. This short review spotlights the very recent applications of C–H functionalization in natural product synthesis and drug synthesis. Some representative examples of natural product total synthesis facilitated by C–H functionalization are classified by C–O, C–C, C–N or C–X bond formation. Three different total syntheses are highlighted in details, in which iterative C–H functionalization strategy is involved. Another example of Merck's synthesis of anacetrapib is also discussed to briefly demonstrate the broad application of C–H functionalization strategy in process chemistry of pharmaceutical industry.
A large number of sesquiterpene quinone/hydroquinone natural products including (+)-ent-chromazonarol have been isolated and received great attention from the synthetic community. Herein, we report a nature-inspired concise synthesis of (+)-ent-chromazonarol in 4 steps from a readily available starting material. The synthesis relied on a Lewis acid mediated cyclization which correctly installed two vicinal stereocenters in one step. This highly efficient synthetic route allows us to further prepare natural product congeners for further biological studies.
A transition-metal-free oxidative N–N bond formation strategy was developed to generate various structurally interesting [1,2,4]triazolo[1,5- a]benzazoles efficiently. The mechanism of the key oxidative N–N bond formation was investigated by using an intramolecular competition reaction. Notably, the first single crystal structure was also obtained to confirm the structure of 2-aryl[1,2,4]triazolo[1,5-a]benzimidazole
Dong Q, Li X, Wang CZ, Xu S, Yuan G, Shao W, Liu B, Zheng Y, Wang H, Lei X, Zhang Z, Zhu B.
Proc Natl Acad Sci U S A. 2018, doi: 10.1073/pnas.1800505115
Epigenetic silencing can be mediated by various mechanisms, and many regulators remain to be identified. Here, we report a genome-wide siRNA screening to identify regulators essential for maintaining gene repression of a CMV promoter silenced by DNA methylation. We identified CSE1L (chromosome segregation 1 like) as an essential factor for the silencing of the reporter gene and many endogenous methylated genes. CSE1L depletion did not cause DNA demethylation. On the other hand, the methylated genes derepressed by CSE1L depletion largely overlapped with methylated genes that were also reactivated by treatment with histone deacetylase inhibitors (HDACi). Gene silencing defects observed upon CSE1L depletion were linked to its nuclear import function for certain protein cargos because depletion of other factors involved in the same nuclear import pathway, including KPNAs and KPNB1 proteins, displayed similar derepression profiles at the genome-wide level. Therefore, CSE1L appears to be critical for the nuclear import of certain key repressive proteins. Indeed, NOVA1, HDAC1, HDAC2, and HDAC8, genes known as silencing factors, became delocalized into cytosol upon CSE1L depletion. This study suggests that the cargo specificity of the protein nuclear import system may impact the selectivity of gene silencing.
Gubu, A. Li, L., Ning, Y., Zhang, X., Lee, S., Feng, M., Li, Q., Lei, X., Jo, K., Tang, X.
Chemistry-A European Journal 2018, 81(2), 298-306
Bioorthogonal metabolic DNA labeling with fluorochromes is a powerful strategy to visualize DNA molecules and their functions. Here, we report the development of a new DNA metabolic labeling strategy enabled by the catalyst-free bioorthogonal ligation using vinyl thioether modified thymidine and o-quinolinone quinone methide. With the newly designed vinyl thioether-modified thymidine (VTdT), we added labeling tags on cellular DNA, which could further be linked to fluorochromes in cells. Therefore, we successfully visualized the DNA localization within cells as well as single DNA molecules without other staining reagents. In addition, we further characterized this bioorthogonal DNA metabolic labeling using DNase I digestion, MS characterization of VTdT as well as VTdT-oQQF conjugate in cell nuclei or mitochondria. This technique provides a powerful strategy to study DNA in cells, which paves the way to achieve future spatiotemporal deciphering of DNA synthesis and functions.
Longestin (KS-505a), a specific inhibitor of phosphodiesterase, is a meroterpenoid that consists of a unique octacyclic terpene skeleton with branched methyl groups at unusual positions (C1 and C12). Biochemical analysis of Lon23, a methyltransferase involved in the biosynthesis of longestin, demonstrated that it methylates homoisopentenyl diphosphate (homo-IPP) to afford (3Z)-3-methyl IPP. This compound, along with IPP, is selectively accepted as extender units by Lon22, a geranylgeranyl diphosphate (GGPP) synthase homologue, to yield dimethylated GGPP (dmGGPP). The absolute configuration of dmGGPP was determined to be (4R,12R) by degradation and chiral GC analysis. These findings allowed us to propose an enzymatic sequence for key steps of the biosynthetic pathway of the unusual homoterpenoid longestin.
Gubu, A.; Li, L.; Ning, Y.; Zhang, X.; Lee, S.; Feng, M.; Li, Q.; Lei, X.; Jo, K.; Tang, X
Chem. Eur. J. 2018, 24, 5895-5900
Bioorthogonal metabolic DNA labeling with fluorochromes is a powerful strategy to visualize DNA molecules and their functions. Here, we report the development of a new DNA metabolic labeling strategy enabled by the catalyst-free bioorthogonal ligation using vinyl thioether modified thymidine and o-quinolinone quinone methide. With the newly designed vinyl thioether-modified thymidine (VTdT), we added labeling tags on cellular DNA, which could further be linked to fluorochromes in cells. Therefore, we successfully visualized the DNA localization within cells as well as single DNA molecules without other staining reagents. In addition, we further characterized this bioorthogonal DNA metabolic labeling using DNase I digestion, MS characterization of VTdT as well as VTdT-oQQF conjugate in cell nuclei or mitochondria. This technique provides a powerful strategy to study DNA in cells, which paves the way to achieve future spatiotemporal deciphering of DNA synthesis and functions
Li X, Shang E, Dong Q, Li Y, Zhang J, Xu S, Zhao Z, Shao W, Lv C, Zheng Y, Wang H, Lei X, Zhu B,* Zhang Z.
J. Biol. Chem. 2018, doi: 10.1074/jbc.RA117.000757.
Regulation of gene expression by epigenetic modifications such as DNA methylation is crucial for developmental and disease processes, including cell differentiation and cancer development. Genes repressed by DNA methylation can be derepressed by various compounds that target DNA methyltransferases, histone deacetylases, and other regulatory factors. However, some additional, unknown mechanisms that promote DNA methylation-mediated gene silencing may exist. Chemical agents that can counteract the effects of epigenetic repression that is not regulated by DNA methyltransferases or histone deacetylases therefore may be of research interest. Here, we report the results of a high-throughput screen using a 308,251-member chemical library to identify potent small molecules that derepress an EGFP reporter gene silenced by DNA methylation. Seven hit compounds were identified that did not directly target bulk DNA methylation or histone acetylation. Analyzing the effect of these compounds on endogenous gene expression, we discovered that three of these compounds (compounds LX-3, LX-4, and LX-5) selectively activate the p38 mitogen-activated protein kinase (MAPK) pathway and derepress a subset of endogenous genes repressed by DNA methylation. Selective agonists of the p38 pathway have been lacking, and our study now provides critical compounds for studying this pathway and p38 MAPK-targeted genes repressed by DNA methylation.
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13‐step Enantioselective Total Synthesis of (+)‐Jungermatrobrunin A
Jinbao Wu, Yuichiro Kadonaga, Benke Hong, Jin Wang, Xiaoguang Lei*
Angew. Chem. Int. Ed. 2019, 58, 10879-10883
A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A (1), possessing a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps via a visible light mediated late‐stage Schenck ene reaction of (‐)‐1α,6α‐diacetoxyjungermannenone C (2). Along the way, a striking UV light induced bicyclo[3.2.1]octene ring rearrangement was applied to afford (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one (4). The photoinduced divergent skeletal rearrangements strongly suggest a possible biogenetic relationship between 1, 2 and 4
Total Synthesis of (±)-Antroquinonol
Xiaoming Wang, Chao Du, Benke Hong, Xiaoguang Lei*
Organic & Biomolecular Chemistry, 2019, 17(7), 1754-1757
We report the total synthesis of (±)-antroquinonol based on a concise and efficient route. Key features include two different strategies to install the required three contiguous stereogenic centers, which not only furnish the desired natural product but also provide natural product congeners for further biological studies.
Recent applications of C–H functionalization in complex molecule synthesis
Chen, K., Lei, X.
Current Opinion in Green and Sustainable Chemistry 2018, 11, 9–14
We have witnessed the striking advancement of C–H functionalization in organic synthesis over the past decade. This short review spotlights the very recent applications of C–H functionalization in natural product synthesis and drug synthesis. Some representative examples of natural product total synthesis facilitated by C–H functionalization are classified by C–O, C–C, C–N or C–X bond formation. Three different total syntheses are highlighted in details, in which iterative C–H functionalization strategy is involved. Another example of Merck's synthesis of anacetrapib is also discussed to briefly demonstrate the broad application of C–H functionalization strategy in process chemistry of pharmaceutical industry.
A Nature-inspired Concise Synthesis of (+)-ent-Chromazonarol
Huang, J.; Lei, X.
Science China Chemistry
A large number of sesquiterpene quinone/hydroquinone natural products including (+)-ent-chromazonarol have been isolated and received great attention from the synthetic community. Herein, we report a nature-inspired concise synthesis of (+)-ent-chromazonarol in 4 steps from a readily available starting material. The synthesis relied on a Lewis acid mediated cyclization which correctly installed two vicinal stereocenters in one step. This highly efficient synthetic route allows us to further prepare natural product congeners for further biological studies.
Syntheses of [1,2,4]triazolo[1,5-a]benzazoles Enabled by the Transition-Metal-Free Oxidative N-N Bond Formation
Shang, E.; Zhang, J.; Bai, J.; Wang, Z.; Li, X.; Zhu, B.; Lei, X.*
Chem. Commun., 2016, 52, 7028
A transition-metal-free oxidative N–N bond formation strategy was
developed to generate various structurally interesting [1,2,4]triazolo[1,5-
a]benzazoles efficiently. The mechanism of the key oxidative N–N bond
formation was investigated by using an intramolecular competition
reaction. Notably, the first single crystal structure was also obtained
to confirm the structure of 2-aryl[1,2,4]triazolo[1,5-a]benzimidazole
Roles of the CSE1L-mediated nuclear import pathway in epigenetic silencing.
Dong Q, Li X, Wang CZ, Xu S, Yuan G, Shao W, Liu B, Zheng Y, Wang H, Lei X, Zhang Z, Zhu B.
Proc Natl Acad Sci U S A. 2018, doi: 10.1073/pnas.1800505115
Epigenetic silencing can be mediated by various mechanisms, and many regulators remain to be identified. Here, we report a genome-wide siRNA screening to identify regulators essential for maintaining gene repression of a CMV promoter silenced by DNA methylation. We identified CSE1L (chromosome segregation 1 like) as an essential factor for the silencing of the reporter gene and many endogenous methylated genes. CSE1L depletion did not cause DNA demethylation. On the other hand, the methylated genes derepressed by CSE1L depletion largely overlapped with methylated genes that were also reactivated by treatment with histone deacetylase inhibitors (HDACi). Gene silencing defects observed upon CSE1L depletion were linked to its nuclear import function for certain protein cargos because depletion of other factors involved in the same nuclear import pathway, including KPNAs and KPNB1 proteins, displayed similar derepression profiles at the genome-wide level. Therefore, CSE1L appears to be critical for the nuclear import of certain key repressive proteins. Indeed, NOVA1, HDAC1, HDAC2, and HDAC8, genes known as silencing factors, became delocalized into cytosol upon CSE1L depletion. This study suggests that the cargo specificity of the protein nuclear import system may impact the selectivity of gene silencing.
Bioorthogonal Metabolic DNA Labelling using Vinyl Thioether-Modified Thymidine and o-Quinolinone Quinone Methide
Gubu, A. Li, L., Ning, Y., Zhang, X., Lee, S., Feng, M., Li, Q., Lei, X., Jo, K., Tang, X.
Chemistry-A European Journal 2018, 81(2), 298-306
Bioorthogonal metabolic DNA labeling with fluorochromes is a powerful strategy to visualize DNA molecules and their functions. Here, we report the development of a new DNA metabolic labeling strategy enabled by the catalyst-free bioorthogonal ligation using vinyl thioether modified thymidine and o-quinolinone quinone methide. With the newly designed vinyl thioether-modified thymidine (VTdT), we added labeling tags on cellular DNA, which could further be linked to fluorochromes in cells. Therefore, we successfully visualized the DNA localization within cells as well as single DNA molecules without other staining reagents. In addition, we further characterized this bioorthogonal DNA metabolic labeling using DNase I digestion, MS characterization of VTdT as well as VTdT-oQQF conjugate in cell nuclei or mitochondria. This technique provides a powerful strategy to study DNA in cells, which paves the way to achieve future spatiotemporal deciphering of DNA synthesis and functions.
Enzymatic formation of a skipped methyl-substituted octaprenyl side chain of longestin (KS-505a): Involvement of homo-IPP as a common extender unit
Taro Ozaki, Sandip S. Shinde, Lei Gao, Ryo Okuizumi, Chengwei Liu, Yasushi Ogasawara, Xiaoguang Lei, Tohru Dairi, Atsushi Minami, Hideaki Oikawa
Angew. Chem. Int. Ed. 2018, 57, 6629-6632
Longestin (KS-505a), a specific inhibitor of phosphodiesterase, is a meroterpenoid that consists of a unique octacyclic terpene skeleton with branched methyl groups at unusual positions (C1 and C12). Biochemical analysis of Lon23, a methyltransferase involved in the biosynthesis of longestin, demonstrated that it methylates homoisopentenyl diphosphate (homo-IPP) to afford (3Z)-3-methyl IPP. This compound, along with IPP, is selectively accepted as extender units by Lon22, a geranylgeranyl diphosphate (GGPP) synthase homologue, to yield dimethylated GGPP (dmGGPP). The absolute configuration of dmGGPP was determined to be (4R,12R) by degradation and chiral GC analysis. These findings allowed us to propose an enzymatic sequence for key steps of the biosynthetic pathway of the unusual homoterpenoid longestin.
Bioorthogonal Metabolic DNA Labelling using Vinyl Thioether-Modified Thymidine and o-Quinolinone Quinone Methide
Gubu, A.; Li, L.; Ning, Y.; Zhang, X.; Lee, S.; Feng, M.; Li, Q.; Lei, X.; Jo, K.; Tang, X
Chem. Eur. J. 2018, 24, 5895-5900
Bioorthogonal metabolic DNA labeling with fluorochromes is a powerful strategy to visualize DNA molecules and their functions. Here, we report the development of a new DNA metabolic labeling strategy enabled by the catalyst-free bioorthogonal ligation using vinyl thioether modified thymidine and o-quinolinone quinone methide. With the newly designed vinyl thioether-modified thymidine (VTdT), we added labeling tags on cellular DNA, which could further be linked to fluorochromes in cells. Therefore, we successfully visualized the DNA localization within cells as well as single DNA molecules without other staining reagents. In addition, we further characterized this bioorthogonal DNA metabolic labeling using DNase I digestion, MS characterization of VTdT as well as VTdT-oQQF conjugate in cell nuclei or mitochondria. This technique provides a powerful strategy to study DNA in cells, which paves the way to achieve future spatiotemporal deciphering of DNA synthesis and functions
Small molecules capable of activating DNA methylation-repressed genes targeted by the p38 mitogen-activated protein kinase pathway
Li X, Shang E, Dong Q, Li Y, Zhang J, Xu S, Zhao Z, Shao W, Lv C, Zheng Y, Wang H, Lei X, Zhu B,* Zhang Z.
J. Biol. Chem. 2018, doi: 10.1074/jbc.RA117.000757.
Regulation of gene expression by epigenetic modifications such as DNA methylation is crucial for developmental and disease processes, including cell differentiation and cancer development. Genes repressed by DNA methylation can be derepressed by various compounds that target DNA methyltransferases, histone deacetylases, and other regulatory factors. However, some additional, unknown mechanisms that promote DNA methylation-mediated gene silencing may exist. Chemical agents that can counteract the effects of epigenetic repression that is not regulated by DNA methyltransferases or histone deacetylases therefore may be of research interest. Here, we report the results of a high-throughput screen using a 308,251-member chemical library to identify potent small molecules that derepress an EGFP reporter gene silenced by DNA methylation. Seven hit compounds were identified that did not directly target bulk DNA methylation or histone acetylation. Analyzing the effect of these compounds on endogenous gene expression, we discovered that three of these compounds (compounds LX-3, LX-4, and LX-5) selectively activate the p38 mitogen-activated protein kinase (MAPK) pathway and derepress a subset of endogenous genes repressed by DNA methylation. Selective agonists of the p38 pathway have been lacking, and our study now provides critical compounds for studying this pathway and p38 MAPK-targeted genes repressed by DNA methylation.