Polyhydroxylated alkaloids (azasugars) have been the subject of intense study due to their glycosidase inhibitory activity and their potential as therapeutic agents. Glycosidases play a vital role in the biosynthesis and processing of the oligosaccharide chains of glycoproteins, molecules that are widely expressed on cell surfaces and are involved in a number of important biological functions and recognition events. The indolizidine swainsonine (SW), for example, is an alpha-mannosidase inhibitor that exhibits encouraging anticancer activity including immune stimulation and the inhibition of tumor growth. The anticancer activity of SW is attributed to its ability to inhibit the formation of certain """"""""complex-type"""""""" cell surface glycoproteins which are found in abundance on tumor cells. SW is currently being studied in clinical trials as an anticancer agent. Based on in vitro and in vivo testing, SW has been found to reduce tumor cell adhesion to the vascular endothelium, inhibit tumor cell invasion through the extracellular matrix, stimulate immune activity against tumor cells, provide protection of the host against the immunosuppressive proteins produced by tumor cells and provide protection of the host against the lethality of several traditional cytotoxic chemotherapeutic agents. Unfortunately, two significant problems stand in the way of the development of this drug. First, it is very difficult to obtain from either natural or synthetic sources. Second, SW causes an undesired inhibition of lysosomal alpha- mannosidases, which induces a reversible phenocopy of the genetic lysosomal storage disease alpha-mannosidosis. This inhibition is also believed to be responsible for other side-effects. The initial results of these trials, while promising, indicate the need for second generation drugs with improved selectivity for the Golgi processing mannosidases and not the lysosomal catabolic mannosidases. Furthermore, these second-generation drugs should be available in large quantities. The overarching goal of the proposed work is to synthesize, in useful quantities, mannosidase-inhibitory analogs of swainsonine with improved prospects for use as anticancer drugs. A secondary goal is to design and synthesize compounds which will help understand the mechanism of the selective inhibition of certain glycoprotein processing enzymes, and to provide compounds of use as biochemical tools (e.g., affinity matrices).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077365-04
Application #
6513393
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Lees, Robert G
Project Start
1999-07-08
Project End
2004-04-30
Budget Start
2002-05-02
Budget End
2004-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$241,715
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Pearson, W H; Hutta, D A; Fang, W K (2000) Azidomercurations of alkenes: mercury-promoted Schmidt reactions. J Org Chem 65:8326-32