SYNTHESIS OF ANTIINFECTIVE AGENTS

Summary

Principal Investigator: Samuel J Danishefsky
Affiliation: Columbia University
Country: USA
Abstract: 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).
Funding Period: 1980-03-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. 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
  2. ncbi 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
  3. ncbi 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
  4. ncbi 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. ncbi 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

Scientific Experts

  • Joseph G Joyce
  • Samuel J Danishefsky
  • Isaac J Krauss
  • Vadim Y Dudkin
  • Xuechen Li
  • Yu Rao
  • Pavel Nagorny
  • David J Maloney
  • Emile J Velthuisen
  • Chihiro Tsukano
  • Rebecca M Wilson
  • Baptiste Aussedat
  • Bernhard Fasching
  • Gong Chen
  • David A Scheinberg
  • Justin S Miller
  • Christophe Antczak
  • Anna S Dudkina
  • Adam C Finnefrock
  • Xudong Geng
  • Hong C Song
  • Michael Chastain
  • Mihirbaran Mandal
  • J David Warren
  • Dionicio R Siegel
  • John W Shiver

Detail Information

Publications10

  1. 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...
  2. ncbi 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
    ....
  3. ncbi 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
    ....
  4. ncbi 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...
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. ncbi 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...