Denny W A, Atwell G J, Roberts P B, Anderson R F, Boyd M, Lock C J, Wilson W R
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
J Med Chem. 1992 Dec 25;35(26):4832-41. doi: 10.1021/jm00104a008.
A series of isomeric 4-[[3-(dimethylamino)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 (ratios of cytotoxicity against wild-type and repair-deficient mammalian cells). Many compounds showed oxygen-sensitive bioreduction resulting in DNA alkylation, while others show oxygen-insensitive modes of action. Of the nitro isomers studied, the 5-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. Structure-activity 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 pKa. 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.
已合成了一系列异构的4-[[3-(二甲氨基)丙基]氨基]硝基喹啉，并将其作为缺氧选择性细胞毒素和缺氧细胞的放射增敏剂进行了评估。这些化合物表现出差异很大的超敏因子（对野生型和修复缺陷型哺乳动物细胞的细胞毒性比率）。许多化合物表现出对氧敏感的生物还原作用，导致DNA烷基化，而其他化合物则表现出对氧不敏感的作用模式。在所研究的硝基异构体中，5-硝基异构体表现出最大的缺氧选择性。随后制备了一系列环取代类似物，以降低其-286 mV的还原电位。构效关系研究表明，取代对还原电位的影响很复杂，是由对硝基的电子效应和空间效应以及对喹啉pKa的影响介导的。两种还原电位较低的化合物，即3-甲基和8-甲基类似物，表现出更高的选择性（在克隆形成试验中分别为47倍和60倍）。作为缺氧细胞放射增敏剂，这两种化合物在该系列中还表现出最高的“体外治疗指数”。尽管具有这些良好的体外特性，但当以最大耐受剂量的60%给药时，这两种化合物对SCCVII肿瘤中的缺氧细胞均无活性。
