The mechanism of the base-catalyzed decomposition of zebularine and similar 2-oxopyrimidine nucleosides has been completely elucidated. The previously elusive electrophilic species generated during the decomposition of the drug(s) has been identified as malonaldehyde. Malonaldehyde is a very reactive species capable of interacting with nucleic acids. The relevance of this phenomenon to the antitumor effect of zebularine and its analogues is under investigation. Some unique five-membered ring gamma-lactones substituted with either myristic or oleic acid ester groups were found to be biologically equivalent to the endogenous protein kinase-C (PK-C) agonist diacylglycerol (DAG). These compounds have a fixed conformation which is presumed to be similar to the conformation adopted by DAG when binding to PK-C. Two long alkyl-ether analogues of these gamma-lactones behaved also as good DAG surrogates. These compounds have the advantage of being hydrolytically stable. Based on these leads, a second generation of rigid DAG analogues was synthesized. Biological evaluation of these new compounds is in progress.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CM006176-07
Application #
3853161
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Division of Cancer Treatment
Department
Type
DUNS #
City
State
Country
United States
Zip Code