NOVEL NUCLEOSIDES AS ANTICANCER AND ANTIVIRAL AGENTS

这项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， 它们在体外和体内的生物活性评价 在荷瘤和病毒感染的动物体内，以及 阐明其生化作用机制(S) 生物活性。将采用的方法包括 制定编制这些文件的方法学 核苷类似物的核磁共振、紫外、质量表征 光谱和其他光谱技术，以及 它们在细胞内的抗癌和抗病毒活性测定 在文化和动物模型中。 近年来，几种化合物的合成及抗肿瘤活性评价 新的3‘-叠氮基和3’-氨基核苷类似物已被问世 在这个实验室里。其中，3‘-氨基-2’， 3‘-二脱氧胞苷(3’-NH_2-CDR，NSC 365107)已被证明是有效的 对L1210、P388和S180肉瘤细胞的抑制作用 体外培养。2‘-脱氧核糖核酸选择性地阻止了细胞毒性。 脱氧胞苷，而不是由其他嘧啶脱氧核糖核酸-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作用 对小鼠L1210和P388白血病的抑制作用。因此， 剂量为20毫克/公斤，每日两次，共9次 连续几天给携带L1210白血病的动物注射3‘-NH2- CDR在80%的治疗动物中产生了治愈作用，而这 在荷瘤小鼠中，该方案的T/C X100值为200。 P388白血病。3‘-NH_2-CDR耐脱氨基 人源性胞苷-脱氧胞苷脱氨酶的纯化 KB细胞；胞苷和2‘-脱氧胞苷都很容易 被这种酶系统脱氨基。基于这些发现， 一系列新型骨肉瘤细胞的制备及化疗试验 提出了一种核苷类似物，其中糖部分是 改性，基膜摩尔分数不同。基因的分子基础 那些具有生物活性的化合物的活性将是 下定决心。

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.