SYNTHETIC MASKED NUCLEOSIDES FOR ANTICANCER STUDIES

根据该研究所的调查结果，（a）几个2 '- 氟-5-取代的ara-C核苷的设计和合成 这种补助金表现出异常显着和选择性抗疱疹 （B）这些核苷之一，FIAC， 经过I期和II期临床试验，证明其上级优于阿糖胞苷A 用于治疗免疫抑制癌症中的带状疱疹感染 患者，和（c）另一种核苷，FMAU，表现出更有效的， 在感染小鼠中抗单纯疱疹1型的活性， 显示出对阿糖胞苷耐药白血病的显著活性， 小鼠，开发5种选定代表的实际合成 结构上与先导化合物FIAC和FIAC相关的核苷类 将进行FMAU。 鉴于我们的发现，我们的某些5-取代木糖基 在C-3'上带有良好离去基团的核苷特别地显示出 有效的体外活性，并且由于这些化合物可能经历邻近的 体内基团置换反应释放C区型核苷 （作为被掩盖的前体）或可能在自己的权利，我们将 合成两类木糖基-嘧啶选择代表 结构上与这些木糖基前导核苷相关， 抗病毒剂和/或抗癌剂。 “内部”抗病毒、生化和化疗协作 对所有七类核苷进行适当评价的研究， 合成的描述。 这些研究应有助于发展 上级目前可用于治疗以下疾病的药物的新药物 癌症和某些病毒性疾病。

On the basis of findings at this Institute that: (a) several 2'- fluoro-5-substitute ara-C nucleosides designed and synthesized under this grant exhibited exceptionally marked and selective antiherpetic activity, both in vitro and in vivo; (b) one of these nucleosides, FIAC, underwent Phase I and II clinical trials and proved to be superior to ara-A for the treatment of Herpes zoster infections in immunosuppressed cancer patients, and (c) another nucleoside, FMAU, exhibited even more potent activity against Herpes simplex type 1 in infected mice and also demonstrated significant activity against ara-C resistant leukemias in mice, development of practical syntheses of selected representatives of 5 classes of nucleosides structurally related to the lead compounds FIAC and FMAU will be undertaken. In view of our findings that certain of our 5-substituted xylosyl nucleosides bearing good leaving groups on C-3' show exceptionally potent activity in vitro and, since such compounds may undergo neighboring group displacement reactions in vivo to liberate area-C type nucleoside (acting as masked precursors) or may be active in their own right, we will synthesize selected representatives of two classes of xylosyl-pyrimidines structurally related to these xylosyl lead nucleosides as potential antiviral and/or anticancer agents. "In-house" antiviral, biochemical and chemotherapeutic collaborative studies for proper evaluation of nucleosides of all seven classes to be synthesized are described. These studies should lead to the development of new agents superior to those drugs currently available for the treatment of cancer and certain viral diseases in man.