We perceive mission of our laboratory to be that of developing new synthetic methods and new strategies which will be of general interest and value in the construction of relatively complex target systems. In our work, we use natural products, an analogs closely related to natural products as focussing devices for our chemical efforts. We deliberately attempt to select a range of targets of varying degrees of complexity. In some instances we are quite consciously confronting difficult synthetic issues which create serious logistical complications. Such syntheses test the limits of capability of the field. From this type of multistep effort we don't ordinarily anticipate generating many analog structures, by synthesis. The second large area on which we will focus will be that of carbohydrate synthesis. We hope to consolidate virtually all of the carbohydrate synthesis effort in our laboratory in HL 25848. This effort will be directed toward cardiac glycosides, cellular adhesion molecules, gangliosides, tumor antigens and glycopeptides. It will involve building upon the new routes developed in our laboratory, to oligosaccharides and other glycoconjugates. We believe that there has been developed a broadly applicable technology. Our goal now is to effect some important improvements and to apply this emerging new capability in the carbohydrate field to a host of important biological problems. From the standpoint of biological focus, a unifying theme is the synthesis of molecules which play an important role in inter and intra cellular signalling. Certainly some of our larger target systems (staurosporine, sialyl LeX and gangliosides) ar in consonance with this theme. In addition we hope to follow up some interesting biological leads which were developed in connection with our successful syntheses of compactin, and KS-501. Thus, the goal systems in which the chemistry will be investigated are: staurosporine, KS-501,502 analogs, trehalozin, F-gitonin, gangliosides (such as GM3 and GM4),sialy LeX, and its analogs, rishirolide, amauromine, pravastatin, and castanospermine. These structures are listed in pictoral form at the end of section AB and are provided with references which provide rapid access to the background literature. From a methodological standpoint we will direct attention to three areas. The firs deals with the construction of novel C-glycosides from 1,2 oxirane an aziridino hexoses. As part of this effort we are looking into the conformational factors which favor glycosyl donating properties of such labile intermediates. Finally we hope to use these findings and the chemistry we have developed to develop a program directed to solic phase syntheses of oligosaccharides an glycoconjugates.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025848-16
Application #
2215913
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1980-01-01
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
16
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
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