This research proposal outlines strategies for the completion of the total synthesis of tirandamycin B and streptolydigin which is patterned after the approach developed for the synthesis of tirandamycin A. The tirandamycins and streptolydigin are members of the dienoyl tetramic acid family of antibiotics isolated from various strains of Streptomyces. Streptolydigin has been shown to selectively inhibit terminal deoxynucleotidyl transferase (TDT), an enzyme present in large quantities in leukemic lymphoblasts, but not in normal leucocytes. TDT is believed to play a crucial role in the cellular metabolism of these cancer cells. It is possible that streptolydigin/tirandamycin or an analog of these natural products will prove effective in the treatment of various leukemias. The proposal also contains sections concerning the development of methodology for the synthesis of spiroketals and piperidones. Using this methodology, we propose to synthesize the spiroketal moieties of the anthelmintic compounds avermectin B1b and B2b, and glycosidase inhibitors 1-deoxynojirimycin, N-methyl-1-deoxynojirimycin, and 1-deoxymannojirimycin. Glycosidase inhibitors are used to characterize lysosomal enzymes involved in the biosynthesis and processing of glycoproteins and to determine the relationship between normal lysomal metabolism and lysosomal disease states. A human lysosomal storage disease is known for each of the glycosidases which are inhibited by these substances and study of their inhibitory activity will aid in understanding the aberrant metabolism associated with these human disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI023688-01
Application #
3135982
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1986-09-01
Project End
1990-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Type
Earth Sciences/Resources
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742