Hypoxia-selective antitumor agents. 6. 4-(Alkylamino)nitroquinolines: a new class of hypoxia-selective cytotoxins.
Hypoxia-selective antitumor agents. 6. 4-(Alkylamino)nitroquinolines: a new class of hypoxia-selective cytotoxins.
复制标题
缺氧选择性抗肿瘤剂。
DOI：
10.1021/jm00104a008
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发表时间：
1992
影响因子：
7.3
通讯作者：
Wilson,WR
中科院分区：
文献类型：
--
作者：
Denny,WA;Atwell,GJ;Roberts,PB;Anderson,RF;Boyd,M;Lock,CJ;Wilson,WR
合成了一系列同分异构体4-[[3-（二甲基氨基）丙基]氨基]硝基喹啉类药物，并对其作为低氧选择性细胞毒素和低氧细胞的放射增敏剂进行了评价。这些化合物显示出广泛不同的超敏因子（对野生型和修复缺陷的哺乳动物细胞的细胞毒性比率）。许多化合物表现出氧敏感生物还原导致DNA烷基化，而其他化合物则表现出氧不敏感的作用模式。在所研究的硝基异构体中，5-硝基表现出最大的缺氧选择性。然后制备了一系列环取代类似物，以降低其286 mV的还原电位。结构活性研究表明，取代对还原电位的影响是复杂的，是由硝基上的电子和空间效应以及对喹啉p的影响介导的。两种低还原电位的化合物，3-和8-甲基类似物，显示出更好的选择性（在克隆实验中分别为47和60倍）。这两种化合物作为缺氧细胞放射增敏剂的“体外治疗指标”也最高。尽管有这些有利的体外特性，但当MTD为60%时，这两种化合物对SCCVII肿瘤中的缺氧细胞都没有活性。
A series of isomeric 4-[[3-(dimethyIamino) propyl] amino] nitroquinolines has been synthesized and evaluated as hypoxia-selective cytotoxins and as radiosensitizers of hypoxic cells. The compounds showed widely-differing hypersensitivity factors (ratiosof cytotoxicity against wildtype and repair-deficient mammalian cells). Many compounds showed oxygen-sensitive bioreduction resulting in DNA alkylation, while othersshow oxygen-insensitive modes of action. Of the nitro isomers studied, the5-nitro showed the greatest hypoxic selectivity. A series of ring-substituted analogues were then prepared, in an effort to lower its reduction potential of-286 mV. Structureactivity studies showed that the effects of substitution on reduction potential were complex, being mediated by electronic and steric effects on the nitro group, as well as by effects on quinoline p. Two compounds of lower reduction potential, the 3-and 8-methyl analogues, showed improved selectivity (47-and 60-fold in a clonogenic assay). These two compounds also showed the highest “in vitro therapeutic indices” of the series as hypoxic cell radiosensitizers. Despite these favorable in vitro properties, neither compound had activity against hypoxic cells in SCCVII tumors when administered at 60% of the MTD.