SYNTHESIS OF ANTITUMOR/VIRAL PYRIMIDINE C-NUCLEOSIDES

化学方法将被开发用于制备六类 C-核苷衍生物，其是合成的或合成的类似物， 具有确定的抗肿瘤和/或抗病毒活性的衍生物或天然的 产品. 烟酰胺核苷的等排体和等电子类似物（1类 （2）人工合成。 这些C-核苷可能显示出有效的抗肿瘤活性， 活性通过抑制IMP-脱氢酶或它们可以增强 作用方式涉及DNA链的其他抗癌药物的活性 破坏 NAD类似物（3类），其中烟酰胺核苷被 将制备1类或2类C-核苷。 这些类似物可以是 比类别1和类别2的C-核苷活性更高。 C-核苷类似物（4类）的有效抗疱疹和潜在的 抗白血病药物FMAU和FEAU将通过修饰 糖部分预先形成的核苷（γ-尿苷）。 新型的环转化反应将被开发并应用于简单的 抗肿瘤抗生素显多霉素和恶嗪霉素的合成及其应用 类似物（类别5和6）来自γ-尿苷。 “内部”生化和化疗合作研究， 对靶向C-核苷的正确评价进行了简要描述。 从这些研究中，结构-活性关系应该是即将到来的 以帮助开发上级目前的新药剂 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.