ENZYME INHIBITORS AS PROTENTIAL ANTICANCER AND ANTIVIRAL DRUGS

对碱催化分解zebularine的机理进行了探讨， 类似的2-氧代嘧啶核苷已被完全阐明。 的 以前难以捉摸的亲电物种产生的过程中， 药物的分解被鉴定为丙二醛。 丙二醛是一种非常活泼的物质，能够与 核酸 这种现象与抗肿瘤作用的相关性 zebularine及其类似物的研究正在进行中。 一些独特的五元环γ-内酯被取代， 肉豆蔻酸或油酸酯基团被发现是生物学上 相当于内源性蛋白激酶-C（PK-C）激动剂 甘油二酯（DAG）。 这些化合物具有固定的构象， 假定与DAG采用的构象相似， 结合PK-C。 这些γ-内酯的两种长烷基醚类似物 也表现得很好 这些化合物的优点是 是水解稳定的。 根据这些线索 合成了刚性DAG类似物的代。 生物 对这些新化合物的评价正在进行中。

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.