SYNTHETIC MASKED NUCLEOSIDES FOR ANTICANCER STUDIES

根据本研究所的调查结果：(A)若干2 双氟5-取代Ara-C核苷的设计与合成 这项捐赠显示出了特别显著和选择性的抗疱疹药物。 体外和体内活性；(B)这些核苷之一，FIAC， 经过I期和II期临床试验，证明优于Ara-A 用于治疗免疫抑制癌症患者的带状疱疹感染 患者和(C)另一种核苷FMAU表现出更强的效力 感染小鼠体内抗单纯疱疹病毒1型的活性 显示出显著的抗阿糖胞苷耐药白血病活性 小鼠，开发选定的5个代表的实用合成 与先导化合物FIAC和FIAC结构相关的核苷类 将进行FMAU。 鉴于我们的发现，我们的某些5-取代木糖醇 在C-3足部含有良好离开基团的核苷表现异常 在体外具有很强的活性，而且由于这些化合物可能会在 体内基团置换反应释放Area-C型核苷 (作为伪装的前体)或可能本身是活跃的，我们将 两类木酰基嘧啶类代表性化合物的合成 结构上与这些木糖基作为潜在的先导核苷 抗病毒和/或抗癌剂。 “内部”抗病毒、生化和化疗协作 关于正确评价所有七类核苷的研究将是 描述了它们的合成过程。这些研究应该导致发展 新的药物优于目前可用于治疗的药物 人类的癌症和某些病毒疾病。

On the basis of findings at this Institute that: (a) several 2 feet-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 feet 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.