Hong C I, An S H, Schliselfeld L, Buchheit D J, Nechaev A, Kirisits A J, West C R
Department of Neurosurgery, Roswell Park Memorial Institute, Buffalo, New York 14263.
J Med Chem. 1988 Sep;31(9):1793-8. doi: 10.1021/jm00117a020.
Three 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-1,2-dipalmitins from L-, D-, and DL-alpha-dipalmitoylphosphatidic acids have been synthesized and their antitumor activity against two ara-C2 resistant L1210 lymphoid leukemia sublines in mice were evaluated. These new prodrugs of ara-C include ara-CDP-L-dipalmitin, ara-CDP-D-dipalmitin, and ara-CDP-DL-dipalmitin. The L and DL isomers produced significant increase in life span (greater than 400%) and four to five long-term survivors (greater than 45 days) out of six animals bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C (I)], while the D isomer displayed a marginal activity (ILS 100-121%). In contrast, the L isomer was completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C (II)]. However, the results demonstrate that the L and DL isomers of ara-CDP-dipalmitin are promising new prodrugs of ara-C with improved efficacy.
已合成了由L-、D-和DL-α-二棕榈酰磷脂酸衍生的三种1-β-D-阿拉伯呋喃糖基胞嘧啶5'-二磷酸-1,2-二棕榈酸酯，并评估了它们对小鼠体内两种对阿糖胞苷（ara-C）耐药的L1210淋巴白血病亚系的抗肿瘤活性。这些阿糖胞苷的新前药包括阿糖胞苷二磷酸-L-二棕榈酸酯、阿糖胞苷二磷酸-D-二棕榈酸酯和阿糖胞苷二磷酸-DL-二棕榈酸酯。L和DL异构体使接种了腹腔植入的部分对阿糖胞苷耐药的L1210亚系[L1210/ara-C（I）]的六只动物中的寿命显著延长（大于400%），并产生了四到五只长期存活者（大于45天），而D异构体显示出微弱的活性（ILS为100 - 121%）。相比之下，L异构体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，结果表明阿糖胞苷二磷酸-L-二棕榈酸酯和阿糖胞苷二磷酸-DL-二棕榈酸酯的L和DL异构体是有前景的阿糖胞苷新前药，其疗效有所提高。
