Sun, L.; Wang, H.; Wang, Z.; He, S.; Chen, S.; Liao, D.; Wang, L.; Yan, J.; Liu, W.; Lei, X.* ; Wang, X. *
Cell 2012, 148, 213-227 (News stories describing this work were highlighted in Chem. & Eng. News 2012 , 5 , 40 ; Nature China 2012 , February 1; Asian Scientist 2012 , January31; and Nature Reviews Molecular Cell Biology , 2012, Feb. 8)
The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-?N?-(4-(?N?-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide?-hereafter referred to as necrosulfonamide?-that specifically blocks […]
Houhua Li, Xiaoming Wang and Xiaoguang Lei*
Angew. Chem. Int. Ed . 2012, 51, 491-495; Angew. Chem . 2012 , 124 , 506-510
Drei?Lycopodium-Alkaloide vom Fawcettimin- und Serratinin-Typ wurden ausgehend von einem gemeinsamen tetracyclischen Spirodiketon-Intermediat in kurzen Totalsynthesen hergestellt (siehe Schema). Das Intermediat selbst wurde über eine Biosynthese-inspirierte transannulare N-C-Knüpfung zum spirokonfigurierten Kohlenstoffzentrum und eine Hydroxy-gelenkte SmI2-vermittelte View Full Article
Daohong Liao, Houhua Li and Xiaoguang Lei*
Org. Lett. 2012, 14, 18-21
An efficient method using silver oxide-mediated oxidation for the synthesis of?ortho-quinone methides has been developed and applied to the biomimetic syntheses of novel trimeric natural products, (±)-schefflone and tocopherol trimers. Further studies of the critical trimerization as well as substrate scope and limitations are also reported. View Full Article
Ting-Chao Chou, Huajin Dong, Xiuguo Zhang, Xiaoguang Lei, John Hartung, Yandong Zhang, Jun Hee Lee, Rebecca M. Wilson, and Samuel J. Danishefsky
PNAS 2011, 108, 14336-1434
We describe herein the discovery of a series of panaxytriol (PXT)-derived polyacetylene small molecules with promising cytoprotective activity. In mouse xenograft models, we have demonstrated the capacity of our synthetic analogs to mitigate a range of cancer therapeutic agent-induced toxicities, including body weight loss, lethality, neurotoxicity, and hematotoxicity. Our PXT analogs have also been found […]
Caspase-1-mediated IL-1β production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-κB-dependent pro-IL-1β transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone […]
Chao Li, Xueliang Yu and Xiaoguang Lei*
Org. Lett. 2010, 12, 4284-4287
A protecting group free and biomimetic total synthesis of (+)-ainsliadimer A has been accomplished in 14 steps from α-santonin. The synthesis relies on a hydrogen bonding promoted [4 + 2]-hetero-Diels?Alder dimerization to afford the key homodimer intermediate, which demonstrates the feasibility of using nonenzymatic conditions to achieve the proposed biosynthesis.
Zhifu Han, Tianhui Niu, Junbiao Chang, Xiaoguang Lei , Mingyan Zhao, Qiang Wang , Wei Cheng , Jinjing Wang , Yi Feng & Jijie Chai
Nature 2010, 464, 1205-1209
Recent studies1, 2, 3, 4, 5 have unequivocally associated the fat mass and obesity-associated (FTO) gene with the risk of obesity. In vitro FTO protein is an AlkB-like DNA/RNA demethylase with a strong preference for 3-methylthymidine (3-meT) in single-stranded DNA or 3-methyluracil (3-meU) in single-stranded RNA6, 7, 8. Here we report the crystal structure of FTO in complex with the mononucleotide 3-meT. FTO comprises an amino-terminal AlkB-like domain and a carboxy-terminal domain with a novel fold. Biochemical assays show that these two domains interact with each other, which is required for FTO catalytic activity. In contrast with the structures of other AlkB members, FTO possesses an extra loop covering one side of the conserved jelly-roll motif. Structural comparison shows that this loop selectively competes with the unmethylated strand of the DNA duplex for binding to FTO, suggesting that it has an important role in FTO selection against double-stranded nucleic acids. The ability of FTO to distinguish 3-meT or 3-meU from other nucleotides is conferred by its hydrogen-bonding interaction with the two carbonyl oxygen atoms in 3-meT or 3-meU. Taken together, these results provide a structural basis for understanding
Phase 2 detoxification enzymes protect against carcinogenesis and oxidative stress. Ginseng ( PANAX spp.) extracts and components were assayed for inducer activity of NQO1 (quinone reductase), a phase 2 enzyme, in Hepa1c1c7 cells. Ginseng extracts were analyzed for ginsenosides and panaxytriol. Korean red PANAX GINSENG extracts demonstrated the most potent phase 2 enzyme induction activity (76,900 U/g dried rhizome powder and 27,800 U/g for two similar preparations). The ginsenoside-enriched HT-1001 American ginseng ( PANAX QUINQUEFOLIUS) extract was the next most potent inducer, with activity of 15,900 U/g, followed by raw American ginseng root with activity of 8700 U/g. Neither a polysaccharide-enriched extract of American ginseng nor a commercial white PANAX GINSENG preparation showed any inducer activity. Pure ginsenosides showed no inducer activity. Protopanaxadiol and protopanaxatriol, deglycosylated ginsenoside metabolic derivatives, showed potent induction activity (approximately 500,000 U/g each). Synthetic panaxytriol was over 10-fold more potent (induction potency 5,760,000 U/g). There was no correlation between ginsenoside content and phase 2 enzyme induction. The most potent inducing red ginseng extract also had the highest panaxytriol content, 120.8 microg/g. We found that ginseng induced NQO1 and that polyacetylenes are the most active components.
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Biomimetic Syntheses of (-)-Gochnatiolides A-C and (-)-Ainsliadimer B
Chao Li, Longyang Dian, Weidong Zhang, and Xiaoguang Lei*
J. Am. Chem. Soc. 2012, 134, 12414-12417
We report the first biomimetic syntheses of (
Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Sun, L.; Wang, H.; Wang, Z.; He, S.; Chen, S.; Liao, D.; Wang, L.; Yan, J.; Liu, W.; Lei, X.* ; Wang, X. *
Cell 2012, 148, 213-227 (News stories describing this work were highlighted in Chem. & Eng. News 2012 , 5 , 40 ; Nature China 2012 , February 1; Asian Scientist 2012 , January31; and Nature Reviews Molecular Cell Biology , 2012, Feb. 8)
The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-?N?-(4-(?N?-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide?-hereafter referred to as necrosulfonamide?-that specifically blocks […]
Total Syntheses of Lycopodium Alkaloids (+)-Fawcettimine, (+)-Fawcettidine, and (-)-8-Deoxyserratinine
Houhua Li, Xiaoming Wang and Xiaoguang Lei*
Angew. Chem. Int. Ed . 2012, 51, 491-495; Angew. Chem . 2012 , 124 , 506-510
Drei?Lycopodium-Alkaloide vom Fawcettimin- und Serratinin-Typ wurden ausgehend von einem gemeinsamen tetracyclischen Spirodiketon-Intermediat in kurzen Totalsynthesen hergestellt (siehe Schema). Das Intermediat selbst wurde über eine Biosynthese-inspirierte transannulare N-C-Knüpfung zum spirokonfigurierten Kohlenstoffzentrum und eine Hydroxy-gelenkte SmI2-vermittelte View Full Article
Efficient Generation of ortho -Quinone Methide: Application to the Biomimetic Syntheses of (±)-Schefflone and Tocopherol Trimers
Daohong Liao, Houhua Li and Xiaoguang Lei*
Org. Lett. 2012, 14, 18-21
An efficient method using silver oxide-mediated oxidation for the synthesis of?ortho-quinone methides has been developed and applied to the biomimetic syntheses of novel trimeric natural products, (±)-schefflone and tocopherol trimers. Further studies of the critical trimerization as well as substrate scope and limitations are also reported. View Full Article
Multifaceted cytoprotection by synthetic polyacetylenes inspired by the ginseng-derived natural product, panaxytriol
Ting-Chao Chou, Huajin Dong, Xiuguo Zhang, Xiaoguang Lei, John Hartung, Yandong Zhang, Jun Hee Lee, Rebecca M. Wilson, and Samuel J. Danishefsky
PNAS 2011, 108, 14336-1434
We describe herein the discovery of a series of panaxytriol (PXT)-derived polyacetylene small molecules with promising cytoprotective activity. In mouse xenograft models, we have demonstrated the capacity of our synthetic analogs to mitigate a range of cancer therapeutic agent-induced toxicities, including body weight loss, lethality, neurotoxicity, and hematotoxicity. Our PXT analogs have also been found […]
Total Synthesis of the G2/M DNA Damage Checkpoint Inhibitor Psilostachyin C
Chao Li , Shanghui Tu, Shuguang Wen, Shan Li, Junbo Chang, Feng Shao, Xiaoguang Lei*
J. Org. Chem. 2011, 76, 3566-3570
View Full Article
Chemical Probing reaveals insights into the signaling mechanism of inflammasome activation
Yi-Nan Gong, Xiaoming Wang, Jiayi Wang, Zhenxiao Yang, Shan Li, Jieling Yang, Liping Liu, Xiaoguang Lei* and Feng Sh
Cell. Res. 2010, 20, 1289-1305
Caspase-1-mediated IL-1β production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-κB-dependent pro-IL-1β transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone […]
A Biomimetic Total Synthesis of (+)-Ainsliadimer A
Chao Li, Xueliang Yu and Xiaoguang Lei*
Org. Lett. 2010, 12, 4284-4287
A protecting group free and biomimetic total synthesis of (+)-ainsliadimer A has been accomplished in 14 steps from α-santonin. The synthesis relies on a hydrogen bonding promoted [4 + 2]-hetero-Diels?Alder dimerization to afford the key homodimer intermediate, which demonstrates the feasibility of using nonenzymatic conditions to achieve the proposed biosynthesis.
Crystal structure of the FTO protein reveals basis for its substrate specificity
Zhifu Han, Tianhui Niu, Junbiao Chang, Xiaoguang Lei , Mingyan Zhao, Qiang Wang , Wei Cheng , Jinjing Wang , Yi Feng & Jijie Chai
Nature 2010, 464, 1205-1209
Recent studies1, 2, 3, 4, 5 have unequivocally associated the fat mass and obesity-associated (FTO) gene with the risk of obesity. In vitro FTO protein is an AlkB-like DNA/RNA demethylase with a strong preference for 3-methylthymidine (3-meT) in single-stranded DNA or 3-methyluracil (3-meU) in single-stranded RNA6, 7, 8. Here we report the crystal structure of FTO in complex with the mononucleotide 3-meT. FTO comprises an amino-terminal AlkB-like domain and a carboxy-terminal domain with a novel fold. Biochemical assays show that these two domains interact with each other, which is required for FTO catalytic activity. In contrast with the structures of other AlkB members, FTO possesses an extra loop covering one side of the conserved jelly-roll motif. Structural comparison shows that this loop selectively competes with the unmethylated strand of the DNA duplex for binding to FTO, suggesting that it has an important role in FTO selection against double-stranded nucleic acids. The ability of FTO to distinguish 3-meT or 3-meU from other nucleotides is conferred by its hydrogen-bonding interaction with the two carbonyl oxygen atoms in 3-meT or 3-meU. Taken together, these results provide a structural basis for understanding
Induction of Chemoprotective Phase 2 Enzymes by Ginseng and its Components
Lee, Lawrence S.; Stephenson, Katherine K.; Fahey, Jed W.; Parsons, Teresa L.; Lietman, Paul S.; Andrade, Adriana S.; Lei, Xiaoguang; Yun, Heedong; Soon, Gaik H.; Shen, Ping; Danishefsky, Samuel; Flexner, Charles
Planta Med. 2009 , 75 , 1129-1133
Phase 2 detoxification enzymes protect against carcinogenesis and oxidative stress. Ginseng ( PANAX spp.) extracts and components were assayed for inducer activity of NQO1 (quinone reductase), a phase 2 enzyme, in Hepa1c1c7 cells. Ginseng extracts were analyzed for ginsenosides and panaxytriol. Korean red PANAX GINSENG extracts demonstrated the most potent phase 2 enzyme induction activity (76,900 U/g dried rhizome powder and 27,800 U/g for two similar preparations). The ginsenoside-enriched HT-1001 American ginseng ( PANAX QUINQUEFOLIUS) extract was the next most potent inducer, with activity of 15,900 U/g, followed by raw American ginseng root with activity of 8700 U/g. Neither a polysaccharide-enriched extract of American ginseng nor a commercial white PANAX GINSENG preparation showed any inducer activity. Pure ginsenosides showed no inducer activity. Protopanaxadiol and protopanaxatriol, deglycosylated ginsenoside metabolic derivatives, showed potent induction activity (approximately 500,000 U/g each). Synthetic panaxytriol was over 10-fold more potent (induction potency 5,760,000 U/g). There was no correlation between ginsenoside content and phase 2 enzyme induction. The most potent inducing red ginseng extract also had the highest panaxytriol content, 120.8 microg/g. We found that ginseng induced NQO1 and that polyacetylenes are the most active components.