Publications:
The Lei Lab

Publications

  
  

Efficient Synthesis of a Novel Resorcyclide as Anticancer Agent Based on Hsp90 inhibition  

Xiaoguang Lei, Samuel J. Danishefsky

Adv. Synth. Catal. 2008 , 350, 1677-1681

  

Biomimetic total synthesis of tricycloillicinone and mechanistic studies toward the rearrangement of prenyl phenyl ethers

Xiaoguang Lei, Mingji Dai, Zihao Hua, Samuel J. Danishefsky

Tetrahedron Lett. 2008 , 49 , 6383-6385

  

(3 R ,9 R ,10 R )-Panaxytriol: a molecular-based nutraceutical with possible application to cancer prevention and treatment

Fay Ng, Heedong Yun, Xiaoguang Lei, Samuel J. Danishefsky, Jed Fahey, Katherine Stephenson, Charles Flexner, Lawrence Lee

Tetrahedron Lett. 2008 , 49 , 7178-7179

  
  
  
  

Identification of Novel Epoxide Inhibitors of HCV Replication Using High-Throughput Screening

Peng, L. F.; Kim, S. S.; Matchacheep, S.; Lei, X .; Su, S.; Lin, W.; Runguphan, W.; Choe, W. H.; Sakamoto, N.; Beeler, A. B.; Porco, J. A., Jr.; Schreiber, S. L.; Chung, R. T.

Antimicrob. Agents Chemother . 2007 , 51 , 3756-3759

Total Synthesis of the Diazobenzofluorene Antibiotic (-)-Kinamycin C1

Xiaoguang Lei and John A. Porco, Jr.  

J. Am. Chem. Soc. 2006 , 128 , 14790-14791( News story describing this work was highlighted in Chem. & Eng. News 2006 , 45 , 9. )

Total Synthesis and Structure Assignment of (+)-Hexacyclinol

John A. Porco Jr., Prof. Dr. , Shun Su, Xiaoguang Lei, Sujata Bardhan, Scott D. Rychnovsky, Prof. Dr.

Angew. Chem. Int. Ed . 2006 , 45 , 5790-5792; Angew. Chem . 2006 , 118 , 5922-5924. (News stories describing this work were reported in Chem. & Eng. News 2006 , 31 , 11 and Nature 2006 , 442 , 492-493)

Stereocontrolled Synthesis of a Complex Library via Elaboration of Angular Epoxyquinol Scaffolds

Xiaoguang Lei, Nava Zaarur, Michael Y. Sherman, John A. Porco, Jr.

J. Org. Chem. 2005 , 70, 6474-6483

  
  
  

Synthesis of a Polymer-Supported Anthracene and Its Application as a Dienophile Scavenger

Xiaoguang Lei and John A. Porco, Jr.

Org. Lett . 2004 , 6 , 795-798

Convergent Synthesis of a Complex Oxime Library Using Chemical Domain Shuffling

Shun Su, Dayle E. Acquilano, Jeevanandam Arumugasamy, Aaron B. Beeler, Erin L. Eastwood, Joshua R. Giguere, Ping Lan, Xiaoguang Lei, Geanna K. Min, Adam R. Yeager, Ya Zhou, James S. Panek, John K. Snyder, Scott E. Schaus, and John A. Porco, Jr.

Org. Lett . 2005 , 7 , 2751-2754

Total Synthesis of the Ubiquitin-Activating Enzyme Inhibitor (+)-Panepophenanthrin

Xiaoguang Lei, Nava Zaarur, Michael Y. Sherman, John A. Porco, Jr.

Angew. Chem. Int. Ed . 2003 , 42 , 3913-3917; Angew. Chem . 2003 , 115 , 4043-4047. (This publication was highlighted as a ※Hot Paper§.)

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

  
Previous Publications:
        

   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. Georg Thieme Verlag KG Stuttgart.New York.

  The highly efficient synthesis of a novel heat shock protein 90 (Hsp90)-based anticancer agent, triazole-cycloproparadicicol, is described. The key step involves a fragment coupling using 'click chemistry' The preliminary biological evaluation of triazole-cycloproparadicicol is also reported.
  Using our high-throughput hepatitis C replicon assay to screen a library of over 8,000 novel diversity-oriented synthesis (DOS) compounds, we identified several novel compounds that regulate hepatitis C virus (HCV) replication, including two libraries of epoxides that inhibit HCV replication (best 50% effective concentration, < 0.5 米M). We then synthesized an analog of these compounds with optimized activity.       
     
      
      
      

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

  

A Biomimetic Total Synthesis of (+)-Ainsliadimer A  

Chao Li, Xueliang Yu and Xiaoguang Lei*

Org. Lett. 2010, 12, 4284-4287

        

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 Shao*

Cell. Res. 2010, 20, 1289-1305

  
  Caspase-1-mediated IL-1汕 production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-百B-dependent pro-IL-1汕 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 is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigericin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses caspase-1 activation triggered by several types of bacterial infection. Bromoxone acts upstream or at the level of the inflammasome in a transcription-independent manner. Bromoxone also inhibits pro-IL-1汕 expression by targeting components upstream of IKK in the TLR-NF-百B pathway. The unique dual activities of bromoxone are shared by the known TAK1 inhibitor that specifically blocks Nalp3 inflammasome activation. Hinted from the mechanistic and pharmacological properties of bromoxone, we further discover that several known NF-百B inhibitors that act upstream of IKK, but not those targeting IKK or IKK downstream, are potent blockers of different NLRs-mediated caspase-1 activation. Our study uncovers a possible non-transcriptional molecular link between the NLR (Nalp3)-mediated inflammasome pathway and TLR-NF-百B signaling, and suggests a potential strategy to develop new anti-inflammatory drugs.
  

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, 14336-14341

  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 to reduce radiation-induced body weight loss and lethality in mouse models. Moreover, several PXT analogs appear to exhibit moderate in vivo antiinflammatory activity as well as in vitro immunoenhancing capabilities. These compounds appear to derive their activity through induction of cancer preventive phase 2 enzymes. The studies described herein suggest that coadministration of a PXT-derived agent with cancer chemotherapeutics or radiation therapy may serve to mitigate a range of therapy-associated toxicities.

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

  
  
  

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

        
  

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

        

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 necrosis downstream of RIP3 activation. An affinity probe derived from necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.

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

  


  

Collective Synthesis of Lycopodium Alkaloids and Tautomer Locking Strategy for the Total Synthesis of ( - )-Lycojapodine A

Houhua Li, Xiaoming Wang, Benke Hong and Xiaoguang Lei*

J. Org. Chem. 2013, 78, 800-821 Featured and Cover Article

Cover Story

The collective total synthesis of Lycopodium alkaloids (+)-fawcettimine, (+)-fawcettidine, (+)-alopecuridine, (-)-lycojapodine A, and (-)-8-deoxyserratinine has been accomplished from a common precursor based on a highly concise route inspired by the proposed biosynthesis of the fawcettimine- and serratinine-type alkaloids. An intramolecular C -alkylation enabled efficient installation of the challenging spiro quaternary carbon center and the aza-cyclononane ring. The preparation of the tricyclic skeleton as well as the establishment of the correct relative stereochemistry of the oxa-quaternary center were achieved by hydroxyl-directed SmI 2-mediated pinacol couplings. An unprecedented tandem transannular N -alkylation and removal of a Boc group was discovered to realize a biosynthesis-inspired process to furnish the desired tetracyclic skeleton. Of particular note is the unique and crucial tautomer locking strategy employed to complete the enantioselective total synthesis of (-)-lycojapodine A. The central step in this synthesis is the late-stage hypervalent iodine oxidant (IBX or Dess每Martin periodinane)/TFA-mediated tandem process, which constructed the previously unknown carbinolamine lactone motif and enabled a biomimetic transformation to generate (-)-lycojapodine A in a single operation.

Challenges and Strategies to the Total Syntheses of Fawcettimine-Type and Serratinine-Type Lycopodium Alkaloids

Wang, X.; Li, H.; Lei, X.*

Synlett. 2013 , DOI: 10.1055/s-0032-1316912 (Invited Synpacts Article).

  
  

A Bioorthogonal Ligation Enabled by Click Cycloaddition of o-Quinolinone Quinone Methide and Vinyl Thioether

Li, Q.; Dong, T.; Liu, X.; Lei, X.*

J. Am. Chem. Soc. 2013 , 135 , 4996-4999 . ( News story describing this work was highlighted in Chem. & Eng. News 2013 , 14 , 37 ).

  Tumor necrosis factor (TNF)-related apoptosis-inducing ligand ( TRAIL ) activates apoptosis through the death receptors DR4 and DR5 . Because of its superior safety profile and high tumor specificity compared to other TNF family members, recombinant soluble TRAIL and agonistic antibodies against its receptors are actively being developed for clinical cancer therapy. Here, we describe the identification and characterization of the small molecules that directly target DR5 to initiate apoptosis in human cancer cells. The activity was initially discovered through a high-throughput chemical screen for compounds that promote cell death in synergy with a small-molecule mimetic of Smac , the antagonist for inhibitor of apoptosis protein. Structure-activity relationship studies yielded a more potent analog called bioymifi, which can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis. Thus, this study identified potential lead compounds for the development of small-molecule TRAIL mimics targeting DR5 for cancer therapy.

    The fawcettimine- and serratinine-type lycopodium alkaloids are a series of structurally complex but related natural products. These alkaloids have been the subjects of intense studies by the synthetic chemistry community, and many elegant strategies have been developed. Herein, we describe the recently disclosed synthetic strategies towards this unique family of natural products, in particular the synthetic endeavors from our research laboratory.

                  

Small Molecule Activation of the TRAIL Receptor DR5 in Human Cancer Cells

Wang, G.; Wang, X.; Yu, H.; Wei, S.; Williams, N.; Holmes, D. L.; Halfmann, R.; Naidoo, J.; Wang, L.; Li, L.; Chen, S.; Harran, P.; Lei, X.* ; Wang, X. *

Nat. Chem. Biol. 2013, 9, 84-89. ( News stories describing this work were highlighted in Chem. & Eng. News 2013 , 2 , 37 ; Nature Asia 2012 , December 24)

  
  Ainsliatrimers A and B are two recently isolated complex sesquiterpenoid natural products that display the unprecedented chemical motifs and remarkable anti-cancer activities. The exact structures as well as the mechanism of anti-cancer action for ainsliatrimers A and B remain to be elucidated. Here we report the first concise and biomimetic syntheses of (-)-ainsliatrimers A and B. Our synthetic endeavor ultimately enabled the unambiguous structural assignments for these two stunningly complex trimers. Preliminary biological studies also revealed that ainsliatrimers A and B significantly inhibited cancer cell growth by inducing apoptosis.

Biomimetic Syntheses and Structural Elucidation of the Apoptosis-Inducing Sesquiterpenoid Trimers: (-)-Ainsliatrimers A and B

Li, C.; Dong, T.; Dian, L.; Zhang, W.; Lei, X.*

Chem. Sci . 2013, 4, 1163-1167 .

  
 

  There is an increasing interest in the use of bioorthogonal ligation to advance biomedical research through selective labeling of biomolecules in living systems. Accordingly, discovering new reactions to expand the toolbox of bioorthogonal chemistry is of particular interest to chemical biologists. Herein we report a new bioorthogonal ligation enabled by click hetero-Diels每Alder (HDA) cycloaddition of in situ-generated o -quinolinone quinone methides and vinyl thioethers. This reaction is highly selective and proceeds smoothly under aqueous conditions. The functionalized vinyl thioethers are small and chemically stable in vivo, making them suitable for use as bioorthogonal chemical reporters that can be effectively coupled to various biomolecules. We utilized this bioorthogonal ligation for site-specific labeling of proteins as well as imaging of bioactive small molecules inside live cells.

  

Absolute Quantification of a Steroid Hormone that Regulates Development in Caenorhabditis elegans

Tie-Mei Li, Jie Chen, Xiangke Li, Xiao-Jun Ding, Yao Wu , Li-Feng Zhao, She Chen, Xiaoguang Lei *,Meng-Qiu Dong *

Anal. Chem. , 2013 , 85 ,9281每9287.