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.
