Resistance-modifying agents.: 11.: Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity.: Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to α1-acid glycoprotein
Resistance-modifying agents.: 11.: Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity.: Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to α1-acid glycoprotein
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DOI：
10.1021/jm040772w
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发表时间：
2004-09-23
影响因子：
7.3
通讯作者：
Griffin, RJ
中科院分区：
文献类型：
--
作者：
Curtin, NJ;Barlow, HC;Griffin, RJ
心血管和抗血栓药物双嘧达莫（DP）由于其对核苷转运的抑制作用，作为抗代谢抗肿瘤药物活性的调节剂具有潜在的治疗用途。然而，DP的活性可通过与急性期血清蛋白α（1）-酸性糖蛋白（AGP）结合而受损。合成了DP类似物，并在存在和不存在5 mg/mL AGP的情况下作为H-3-胸苷摄取到L1210白血病细胞中的抑制剂进行了评价。鉴定了具有与DP相似效力的化合物，其中4，8-位的哌啶基取代基被4 '-甲氧基苄基氨基、3'，4 '-二甲氧基苄基氨基或胡椒基氨基取代。在DP的2，6-位上的二乙醇氨基被烷基氨基或烷氧基取代基取代是可以容忍的，尽管侧链中需要至少一个含氧官能团（羟基或烷氧基）以获得与DP相当的活性。而AGP完全消融DP的活性，大多数新的化合物合成的保留显着的活性在过量的AGP的存在下，虽然在4，8-位置的哌啶基的N-甲基苄基氨基取代基的替代，在某些情况下，恢复敏感性AGP。选择的化合物已被证明可以防止由核苷补救介导的抗叶酸剂细胞毒性的补救。
The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of H-3-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.