SYNTHESIS OF ANTITUMOR/VIRAL PYRIMIDINE C NUCLEOSIDES

将开发六种化学方法来制备六类 C-核苷衍生物是两种人工合成的 具有公认的抗肿瘤和/或抗病毒活性的衍生物或天然的 产品。 烟酰胺核苷的同位异构体和等电子类似物(1类 2)意志的综合。这些C-核苷可能显示出强大的抗肿瘤作用。 通过抑制IMP脱氢酶的活性，或者它们可能会增强 作用方式涉及DNA链的其他抗癌药物的活性 颠覆。 烟酰胺核苷被取代的NAD类似物(3类) 将制备1类或2类C-核苷。这些类比可能是 比第1类和第2类的C-核苷活性更高。 有效的抗疱疹药物的C-核苷类似物(4类)和潜在的 抗白血病药物FMAU和FEAU将通过以下修饰合成 糖基上预先形成的核苷(伽马-尿苷)。 新型环转化反应将被开发并应用于手工品 抗肿瘤抗生素展多霉素和恶唑霉素的合成及其应用 来自伽玛尿苷的类似物(5类和6类)。 “内部”生化和化疗协作研究 对目标C-核苷的正确评价作了简要描述。 从这些研究中，结构-活性关系应该是可行的 帮助开发比现有代理商更好的新代理商 可用于治疗人类癌症和/或病毒感染。

Chemical methods will be developed for the preparation of six classes of C-nucleoside derivatives which are close analogs of either synthetic derivatives with established antitumor and/or antiviral activity or natural products. Isosteres and isoelectronic analogs of nicotinamide nucleoside (classes 1 and 2) will by synthesized. These C-nucleosides may show potent antitumor activity by inhibiting IMP-dehydrogenase or they may potentiate the activity of other anticancer drugs whose mode of action involves DNA strand disruption. NAD analogs (class 3) in which the nicotinamide nucleoside is replaced by a class 1 or class 2 C-nucleoside will be prepared. These analogs may be more active that the C-nucleosides of classes 1 and 2. C-Nucleoside analogs (class 4) of the potent antiherpetic and potential antileukemic agents, FMAU and FEAU, will be synthesized by modification of a preformed nucleoside (gamma-uridine) at the sugar moiety. Novel ring transformation reactions will be developed and applied to facile synthesis of antitumor antibiotics, showdomycin and oxazinomycin, and their analogs (classes 5 and 6) from Gamma-uridine. "In house" biochemical and chemotherapeutic collaborative studies for proper evaluation of the targeted C-nucleosides are described briefly. From these studies, structure-activity relationships should be forthcoming to aid in the development of new agents superior to those currently available for the treatment of cancer and/or viral infection in man.