NOVEL NUCLEOSIDES AS ANTICANCER AND ANTIVIRAL AGENTS

本研究的目标是设计和合成一种 一系列潜在的抗癌和抗病毒核苷类似物， 体外和体内生物活性评价 在荷瘤和病毒感染的动物体内， 阐明其生物化学作用机制 生物活性 拟采用的方法包括 制订编写这些报告的方法 核苷类似物，它们的NMR、UV、质谱表征 光谱和其他光谱技术，以及 细胞内抗癌和抗病毒活性的测定 文化和动物模型。 最近，几个合成和评价 新的3 ′-叠氮基和3 ′-氨基核苷类似物已被提出 在这个实验室里。 在这些化合物中，3 ′-氨基-2 ′， 3'-NH2-CdR，NSC 365107， 对L1210、P388和肉瘤180细胞的抑制作用 体外 细胞毒性被2 '- 脱氧胞苷，而不是由其他嘧啶脱氧核糖或 核糖核苷或嘌呤核苷。 更重要的是，3 '- 2 ′-脱氧胞苷的氨基类似物具有显著的抗癌活性 在小鼠中抗L1210和P388白血病的活性。 因此 当以20 mg/Kg的剂量每天两次给药， 对携带L1210白血病的动物，3 '-NH 2- CdR在80%的治疗动物中产生了治愈效果， 方案在荷瘤小鼠中产生200的T/C X 100值， P388白血病。 3 '-NH 2-CdR对脱氨基有抗性， 纯化的人源胞苷-脱氧胞苷脱氨酶 KB细胞;胞苷和2 '-脱氧胞苷都很容易 被这种酶系统脱氨。 根据这些发现， 制造和化学治疗试验的一个新的系列， 提出了核苷类似物，其中糖部分是 改性和基础moeity变化。 的分子基础 这些具有生物活性的化合物的活性将是 测定

This investigation has as its goal the design and synthesis of a series of potential anticancer and antiviral nucleoside analogues, the evaluation of their biological activities both in vitro and in vivo in tumor-bearing and virus infected animals, and the elucidation of the biochemical mechanism of action(s) of their biological activity. The approaches to be employed include the development of methodology for the preparation of these nucleoside analogues, their characterization by NMR, UV, mass spectrum, and other spectrometric techniques, and the determination of their anticancer and antiviral activities in cell culture and in animal models. Recently, the synthesis and antineoplastic evaluation of several new 3'-azido and 3'-amino nucleoside analogues have been carried out in this laboratory. Among these compounds, 3'-amino-2', 3'dideoxycytidine (3'-NH2-CdR, NSC 365107) has shown potent inhibitory effects against L1210, P388 and Sarcoma 180 cells in vitro. The cytotoxicity was selectively prevented by 2'- deoxycytidine, and not by other pyrimidine deoxyribo- or ribonucleosides, or purine nucleosides. More importantly, the 3'- amino analogue of 2'-deoxycytidine exhibits marked anticancer activity against both L1210 and P388 leukemias in mice. Thus when given in a dose of 20 mg/Kg twice a day for nine consecutive days to animals bearing the L1210 leukemia, 3'-NH2- CdR produced cures in 80% of the treated animals, and this regimen yielded a T/C X 100 value of 200 in mice bearing the P388 leukemia. 3'-NH2-CdR is resistant to deamination by purified cytidine-deoxycytidine deaminase derived from human KB cells; both cytidine and 2'-deoxycytidine are readily deaminated by this enzyme system. Based on these findings, the fabrication and chemotherapeutic testing of a novel series of nucleoside analogues are proposed in which the sugar portion is modified and the base moeity varied. The molecular basis for the activity of those compounds that are biologically active will be determined.