ENZYME INHIBITORS AS PROTENTIAL ANTICANCER AND ANTIVIRAL DRUGS

1-(2‘-deoxy-BETA-D-ribofuranosyl)-1，2-Dihydropyrimidine-2-one-5’- 单磷酸盐(2‘-脱氧泽布灵单磷酸)是一种非常 有效的脱氧胞苷脱氨酶抑制剂。母体核苷是 由一种新的合成方法制备。一部大规模改编的 2‘-脱氧泽布林的合成效果良好。5‘-二氢呋喃类化合物的合成 用于生物测试的足够量的单磷酸盐在 进步。与5‘-单磷酸的比较研究 四氢尿苷是计划中的。 合成了大量的单丁内酯和双丁内酯，并 在它们激活的方式上表现出非常立体的选择性 蛋白激酶C(PK-C)。这些化合物的构象功能 甘油二酯的限制性类似物。所达到的效力水平 现在是亚微磨牙。更精细的结构-活性分析是 预计将产生纳摩尔浓度下有效的化合物。这 结构上的重要信息将用于PK-C的设计 抑制剂。

1-(2'-deoxy-BETA-D-ribofuranosyl)-1,2-Dihydropyrimidine-2-one-5'- monophosphate (2'-deoxyzebularine monophosphate) was identified as a very potent inhibitor of deoxycytidilate deaminase. The parent nucleoside was prepared by a new synthetic approach. A large-scale adaptation of the synthesis of 2'-deoxyzebularine worked well. Synthesis of the 5'- monophosphate in sufficient amounts for biological testing is in progress. Comparative studies with the 5'-monophosphate of tetrahydrouridine are planned. A large number of mono- and bis-butyrolactones have been synthesized and shown to be very stereoselective in the manner in which they activate protein kinase C (PK-C). These compounds function as conformationally constrained analogues of diacylglycerol. The level of potency achieved is now submicromolar. A more refined structure-activity analysis is expected to yield compounds effective at nanomolar concentrations. This structurally vital information will be put to use in the design of PK-C inhibitors.