The chemical structures of the first and last products formed during the base-catalyzed decomposition of zebularine have been elucidated. Zebularine is a 2-oxopyrimidine nucleoside with potent cytidine deaminase inhibitory activity. Zebularine is unique in that it is also endowed with good in vivo antitumor activity. This study attempts to identify the elusive electrophilic species that is formed during the decomposition of this drug and which could be responsible for its antitumor effect. The 5-fluoro analogue was also studied and found to behave similarly. The synthesis of a series of conformationally constrained analogues of diacylglycerol was achieved. One of the many myristoylated 2-deoxypentonolactones synthesized was identified as equipotent to DAG in its capacity to compete for the phorbol receptor of protein kinase C (PK-C). This compound probably represents the conformation in which DAG binds to PK-C and hence this information could be of use for the design of either agonists or antagonists to PK-C. Some ether-containing analogues of the acyl-containing 2-deoxypentonolactones were synthesized. Complete biological evaluation is in progress.
