Nucleoside conjugates. 11. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine and cytidine conjugates of thioether lipids.
Nucleoside conjugates. 11. Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine and cytidine conjugates of thioether lipids.
复制标题
核苷缀合物。
DOI：
--
复制
发表时间：
1990
影响因子：
7.3
通讯作者：
C. West
中科院分区：
文献类型：
--
作者：
C. Hong;A. J. Kirisits;A. Nechaev;D. J. Buchheit;C. West
制备了五种 1-β-D-阿拉伯呋喃糖基胞嘧啶缀合物和两种通过焦磷酸二酯键连接的硫醚脂质（1-S-烷基硫代甘油）胞苷缀合物，并评估了它们对小鼠中 ara-C2 敏感（L1210/0）和两种 ara-C 耐药 L1210 淋巴白血病亚系的抗肿瘤活性。 ara-C的这些前药包括ara-CDP-rac-1-S-十六烷基-2-O-棕榈酰基-1-硫代甘油(8a)、ara-CDP-rac-1-S-十八烷基-2-O-棕榈酰硫代甘油(8b)和ara-CDP-rac-1-S-十八烷基-2-O-甲基(或乙基)， -十六烷基)硫代甘油(8c-e)。胞苷缀合物包括 CDP-rac-1-S-十八烷基-2-O-棕榈酰（或-甲基）-1-硫代甘油（9a 和 9b）。缀合物的超声处理溶液以胶束盘的形式存在（尺寸0.01-0.04微米）。单剂量（200-400mg/kg）8a和8b使患有腹膜内植入L1210/0白血病的小鼠的寿命显着延长（257-371%）。相反，缀合物 8c-e 效果较差（ILS 19-75%），胞苷缀合物（9a 和 9b）无效。尽管发现8a和8b对于腹腔注射部分ara-C抗性L1210亚系[L1210/ara-C(I)]的高比例小鼠具有治疗作用，但它们对脱氧胞苷激酶缺陷的ara-C抗性L1210亚系[L1210/ara-C(II)]完全无效。然而，目前的结果与之前的结果一起表明，8a 和 8b 是有前途的新 ara-C 前药，具有改善的功效。
Five 1-beta-D-arabinofuranosylcytosine conjugates and two cytidine conjugates of thioether lipids (1-S-alkylthioglycerols) linked by a pyrophosphate diester bond have been prepared and their antitumor activity against an ara-C2 sensitive (L1210/0) and two ara-C resistant L1210 lymphoid leukemia sublines in mice were evaluated. These prodrugs of ara-C include ara-CDP-rac-1-S-hexadecyl-2-O-palmitoyl-1-thioglycerol (8a), ara-CDP-rac-1-S-octadecyl-2-O-palmitoylthioglycerol (8b), and ara-CDP-rac-1-S-octadecyl-2-O-methyl(or -ethyl, -hexadecyl)thioglycerols (8c-e). The cytidine conjugates include CDP-rac-1-S-octadecyl-2-O-palmitoyl(or -methyl)- 1-thioglycerols (9a and 9b). Sonicated solutions of the conjugates existed in the form of micellar disks (size 0.01-0.04 microns). Single doses (200-400 mg/kg) of 8a and 8b produced significant increase in life span (257-371%) in mice bearing ip implanted L1210/0 leukemia. In contrast, conjugates 8c-e were less effective (ILS 19-75%) and cytidine conjugates (9a and 9b) were ineffective. Even though 8a and 8b were found to be curative in a high percentage of mice bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C(I)], they were completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C(II)]. However, the present results, together with the previous, demonstrate that 8a and 8b are promising new prodrugs of ara-C with improved efficacy.