Hong C I, Kirisits A J, Nechaev A, Buchheit D J, West C R
Department of Neurosurgery, Roswell Park Memorial Institute, Buffalo, New York 14263.
J Med Chem. 1990 May;33(5):1380-6. doi: 10.1021/jm00167a016.
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.
已制备出五种通过焦磷酸二酯键连接的硫醚脂质（1 - S - 烷基硫代甘油）的1 - β - D - 阿拉伯呋喃糖基胞嘧啶共轭物和两种胞苷共轭物，并评估了它们对小鼠体内一株对阿糖胞苷敏感的（L1210/0）以及两株对阿糖胞苷耐药的L1210淋巴细胞白血病亚系的抗肿瘤活性。这些阿糖胞苷前药包括阿糖胞苷二磷酸 - rac - 1 - S - 十六烷基 - 2 - O - 棕榈酰 - 1 - 硫代甘油（8a）、阿糖胞苷二磷酸 - rac - 1 - S - 十八烷基 - 2 - O - 棕榈酰硫代甘油（8b）以及阿糖胞苷二磷酸 - rac - 1 - S - 十八烷基 - 2 - O - 甲基（或 - 乙基、 - 十六烷基）硫代甘油（8c - e）。胞苷共轭物包括胞苷二磷酸 - rac - 1 - S - 十八烷基 - 2 - O - 棕榈酰（或 - 甲基） - 1 - 硫代甘油（9a和9b）。共轭物的超声处理溶液以胶束盘的形式存在（尺寸为0.01 - 0.04微米）。单剂量（200 - 400 mg/kg）的8a和8b使腹腔注射植入L1210/0白血病的小鼠的寿命显著延长（257 - 371%）。相比之下，共轭物8c - e效果较差（生命延长率为19 - 75%），而胞苷共轭物（9a和9b）则无效。尽管发现8a和8b能使腹腔注射植入部分对阿糖胞苷耐药的L1210亚系[L1210/ara-C(I)]的小鼠中有很高比例得到治愈，但它们对脱氧胞苷激酶缺陷的阿糖胞苷耐药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是有前景的新型阿糖胞苷前药，其疗效有所提高。
