SYNTHESIS OF ANTIINFECTIVE AGENTS

Summary

Principal Investigator: Samuel J Danishefsky
Affiliation: Columbia University
Country: USA
Abstract: [unreadable] DESCRIPTION (provided by applicant): The long term goals of our laboratory involve the achievement of advances in the capabilities in chemical synthesis and the applications of these advances to problems of biological and even medicinal import. At the chemistry level, we select novel and challenging small molecule natural products structures, which will serve to stimulate and exemplify the value of new strategies and new reaction methodologies. In this facet of our "small molecule" work, we place particular emphasis on conciseness of approach, convergence, and stereocontrol. In parallel we have a program addressed to the chemical synthesis of complex oligosaccharides, in the context of polypeptide or protein like conjugates. In this effort, we place particular emphasis on novel glycosylation protocols and, seek out particular retrosynthetic disconnections and protection strategies which enable conciseness of the synthetic effort. In this program we seek to enlarge upon our capacity to build complex oligosaccharides into the context of substantial polypeptide or even protein settings. For this AI-16943-25-29 grant period, we have identified eight (8) programs for exploration: (1) migrastatin - as its name implies, this compound is reported to prevent tumor cell migration. As such, it might provide the basis for a significant drug candidate in angiogenesis; (2) brasilicardin - an immunosuppressive agent; (3) garsubellin - this compound is exemplary of a fascinating series of non-peptidal small molecules which exhibit neuronal growth factor activity; (4)tashironin - this compound is substantially dissimilar to garsubellin. It also exhibits non-peptidal NGF activity; (5) NG0187 - this compound is a polyoxygenated steroid-like system which also exhibits non-peptidal nerve growth factor activity; (6) Asparagine linked glycopolypeptide constructs which simulate the key structural features of PSA (prostate specific antigen); (7) the synthesis of constructs which simulate the key features of GP120. Aside from the chemical challenge, implicit in this goal is the hope to induce an antibody response which could be of value in progression of the evolution of AIDS disease; (8) A long term goal of the complex glycoconjugate program is the total synthesis of a functional erythropoietin (EPO). [unreadable] [unreadable]
Funding Period: 1980-03-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. pmc Solving the convergence problem in the synthesis of triantennary N-glycan relevant to prostate-specific membrane antigen (PSMA)
    Maciej A Walczak
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 134:16430-3. 2012
  2. pmc Promising general solution to the problem of ligating peptides and glycopeptides
    Ping Wang
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 132:17045-51. 2010
  3. pmc Revisiting oxytocin through the medium of isonitriles
    Ting Wang
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 134:13244-7. 2012
  4. pmc Engineering of therapeutic polypeptides through chemical synthesis: early lessons from human parathyroid hormone and analogues
    Suwei Dong
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 134:15122-9. 2012
  5. pmc Cascade resulting in the reductive ethynylation of aldehydes: dissection of its components
    Dongjoo Lee
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 132:4427-30. 2010
  6. pmc Toward fully synthetic, homogeneous glycoproteins: advances in chemical ligation
    Yu Yuan
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
    Biopolymers 94:373-84. 2010
  7. pmc Total synthesis of (+/-)-aplykurodinone-1: traceless stereochemical guidance
    Yandong Zhang
    Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027, USA
    J Am Chem Soc 132:9567-9. 2010
  8. pmc A model for the dynamics of ultrasound contrast agents in vivo
    Shengping Qin
    Department of Biomedical Engineering, University of California, 451 East Health Sciences Drive, Davis, California 95616, USA
    J Acoust Soc Am 128:1511-21. 2010
  9. pmc Encouraging progress in the ω-aspartylation of complex oligosaccharides as a general route to β-N-linked glycopolypeptides
    Ping Wang
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, United States
    J Am Chem Soc 133:1597-602. 2011
  10. pmc Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin
    Nicolas Lecomte
    Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 108:15074-8. 2011

Scientific Experts

  • Joseph G Joyce
  • Samuel J Danishefsky
  • Pavel Nagorny
  • Ping Wang
  • Rebecca M Wilson
  • Isaac J Krauss
  • Baptiste Aussedat
  • Xuechen Li
  • Bernhard Fasching
  • Yu Yuan
  • Vadim Y Dudkin
  • Neeraj Sane
  • Suwei Dong
  • Ting Wang
  • Maciej A Walczak
  • Xiangyang Wu
  • Nicolas Lecomte
  • Guangli Yang
  • Ouathek Ouerfelli
  • Malcolm A S Moore
  • Jin Chen
  • Yandong Zhang
  • Dongjoo Lee
  • Thordur Oskarsson
  • Shengping Qin
  • Yu Rao
  • Woo Han Kim
  • Mihirbaran Mandal
  • David J Maloney
  • Emile J Velthuisen
  • Chihiro Tsukano
  • Jennifer L Stockdill
  • Shiying Shang
  • Paul A Vadola
  • Peter K Park
  • Jianfeng Li
  • Thomas J Gardella
  • Eric Johnston
  • Zhongping Tan
  • Akira Maeda
  • Thomas Dean
  • Robert Downey
  • Jon T Njardarson
  • Jianglong Zhu
  • Joan Massague
  • Lucy Perez
  • Danhua Xiao
  • Katherine W Ferrara
  • Qian Wan
  • Jun Hee Lee
  • Gong Chen
  • David A Scheinberg
  • Justin S Miller
  • Christophe Antczak
  • Anna S Dudkina
  • Adam C Finnefrock
  • Xudong Geng
  • Hong C Song
  • Michael Chastain
  • J David Warren
  • Dionicio R Siegel
  • John W Shiver

Detail Information

Publications35

  1. pmc Solving the convergence problem in the synthesis of triantennary N-glycan relevant to prostate-specific membrane antigen (PSMA)
    Maciej A Walczak
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 134:16430-3. 2012
    ..Two strategies for installation of sialylated antennae are explored, and both approaches converge on a global glycosylation step that delivers the desired tetradecasaccharide in good yields...
  2. pmc Promising general solution to the problem of ligating peptides and glycopeptides
    Ping Wang
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 132:17045-51. 2010
    ..These ligations are conducted with minimal α-epimerization in the C-terminal group and allow for the coupling of N-terminal and C-terminal glycopeptides en route to homogeneous glycoproteins...
  3. pmc Revisiting oxytocin through the medium of isonitriles
    Ting Wang
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 134:13244-7. 2012
    ..The NMR spectra of oxytocin and dihydrooxytocin suggest a high level of preorganization in the latter, perhaps favoring oxidative folding...
  4. pmc Engineering of therapeutic polypeptides through chemical synthesis: early lessons from human parathyroid hormone and analogues
    Suwei Dong
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 134:15122-9. 2012
    ..Application of chemical synthesis to gain access to high purity hPTH as well as more stable analogues was accomplished through a menu of extended NCL followed by metal free dethiylation...
  5. pmc Cascade resulting in the reductive ethynylation of aldehydes: dissection of its components
    Dongjoo Lee
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 132:4427-30. 2010
    ..The differential roles played by the various elements of the process were demonstrated through dissection experiments...
  6. pmc Toward fully synthetic, homogeneous glycoproteins: advances in chemical ligation
    Yu Yuan
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
    Biopolymers 94:373-84. 2010
    ....
  7. pmc Total synthesis of (+/-)-aplykurodinone-1: traceless stereochemical guidance
    Yandong Zhang
    Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, New York 10027, USA
    J Am Chem Soc 132:9567-9. 2010
    ....
  8. pmc A model for the dynamics of ultrasound contrast agents in vivo
    Shengping Qin
    Department of Biomedical Engineering, University of California, 451 East Health Sciences Drive, Davis, California 95616, USA
    J Acoust Soc Am 128:1511-21. 2010
    ..Dynamics of UCAs with a shell of lipid, polymer, albumin and liquid are investigated for typical therapeutic ultrasound pulses. The effects of liquid compressibility and shell and tissue parameters are analyzed...
  9. pmc Encouraging progress in the ω-aspartylation of complex oligosaccharides as a general route to β-N-linked glycopolypeptides
    Ping Wang
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, United States
    J Am Chem Soc 133:1597-602. 2011
    ..Various mechanisms for oxidative coupling are proposed...
  10. pmc Emergence of potent inhibitors of metastasis in lung cancer via syntheses based on migrastatin
    Nicolas Lecomte
    Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
    Proc Natl Acad Sci U S A 108:15074-8. 2011
    ..2% and 99.3%, respectively). Together these very encouraging findings suggest that these analogs have promise as potent antimetastatic agents in lung cancer...
  11. pmc Probing the frontiers of glycoprotein synthesis: the fully elaborated β-subunit of the human follicle-stimulating hormone
    Pavel Nagorny
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
    Angew Chem Int Ed Engl 51:975-9. 2012
  12. pmc Total synthesis of the α-subunit of human glycoprotein hormones: toward fully synthetic homogeneous human follicle-stimulating hormone
    Baptiste Aussedat
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 134:3532-41. 2012
    ..The other contains dodecamer oligosaccharides at these same sites. The dodecamer sugar is a consensus sequence incorporating the key features associated with human glycoproteins...
  13. pmc A fascinating journey into history: exploration of the world of isonitriles en route to complex amides
    Rebecca M Wilson
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
    Angew Chem Int Ed Engl 51:2834-48. 2012
    ..We further describe the application of these methods to the syntheses of complex systems, including the cyclic peptide cyclosporine A, constrained peptide systems, and heterocycles...
  14. pmc Diverted total synthesis leads to the generation of promising cell-migration inhibitors for treatment of tumor metastasis: in vivo and mechanistic studies on the migrastatin core ether analog
    Thordur Oskarsson
    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 132:3224-8. 2010
    ..Both in vivo and in vitro studies indicate that ME exhibits a concentration-dependent inhibitory effect on migration of breast cancer cells...
  15. pmc Improved dienophilicity of nitrocycloalkenes: prospects for the development of a trans-Diels-Alder paradigm
    Woo Han Kim
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 131:12576-8. 2009
    ....
  16. ncbi Fully synthetic carbohydrate HIV antigens designed on the logic of the 2G12 antibody
    Isaac J Krauss
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA
    J Am Chem Soc 129:11042-4. 2007
  17. ncbi Total synthesis of (+)-suaveolindole: establishment of its absolute configuration
    Emile J Velthuisen
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA
    J Am Chem Soc 129:10640-1. 2007
  18. ncbi Total synthesis of (+)-isomigrastatin
    Isaac J Krauss
    The Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA
    Angew Chem Int Ed Engl 46:5576-9. 2007
  19. ncbi Conformational locking through allylic strain as a device for stereocontrol--total synthesis of grandisine A
    David J Maloney
    Laboratory of Bioorganic Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Angew Chem Int Ed Engl 46:7789-92. 2007
  20. ncbi Differentiation of nonconventional "carbanions"-the total synthesis of nemorosone and clusianone
    Chihiro Tsukano
    Laboratory of Bioorganic Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Angew Chem Int Ed Engl 46:8840-4. 2007
  21. pmc Toward a prostate specific antigen-based prostate cancer diagnostic assay: preparation of keyhole limpet hemocyanin-conjugated normal and transformed prostate specific antigen fragments
    Vadim Y Dudkin
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 130:13598-607. 2008
    ..These glycopeptide/KLH conjugates were then used for antibody generation...
  22. pmc An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions
    Joseph G Joyce
    Department of Vaccines Basic Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
    Proc Natl Acad Sci U S A 105:15684-9. 2008
    ....
  23. pmc Toward fully synthetic homogeneous beta-human follicle-stimulating hormone (beta-hFSH) with a biantennary N-linked dodecasaccharide. synthesis of beta-hFSH with chitobiose units at the natural linkage sites
    Pavel Nagorny
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 131:5792-9. 2009
    ....
  24. pmc Thio FCMA intermediates as strong acyl donors: a general solution to the formation of complex amide bonds
    Yu Rao
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10065, USA
    J Am Chem Soc 131:12924-6. 2009
    ..Novel methodology for the formation of amide bonds under neutral conditions is described. Evidence is presented that the active acyl donors are thio FCMA intermediates, generated from the reactions of thioacids with isonitriles...
  25. ncbi Applications of total synthesis to problems in neurodegeneration: Fascinating chemistry along the way
    Rebecca M Wilson
    Laboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA
    Acc Chem Res 39:539-49. 2006
    ..Our focus has been on agents derived from natural-product leads and natural products themselves prepared through total synthesis. Herein, we describe some of the chemistry as well as interesting observations made along the way...