Jenkins T C, Naylor M A, O'Neill P, Threadgill M D, Cole S, Stratford I J, Adams G E, Fielden E M, Suto M J, Stier M A
Medical Research Council Radiobiology Unit, Didcot, Oxfordshire, U.K.
J Med Chem. 1990 Sep;33(9):2603-10. doi: 10.1021/jm00171a040.
alpha-[(1-Aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanols, of general formula ImCH2CH(OH)CH2NCR1R2CR3R4, where Im = 2-nitroimidazole and R1, R2, R3, R4 = H, Me, are radiosensitizers and selective bioreductively activated cytotoxins toward hypoxic tumor cells in vitro and in vivo. Treatment of the aziridines with hydrogen halide in acetone or aqueous acetone gave the corresponding 2-haloethylamines of general formula ImCH2CH(OH)CH2(+)-NH2CR1R2CR3R4X X-, where R1, R2, R3, R4 = H, Me, and X = F, Cl, Br, I. These 2-haloethylamines were evaluated as prodrugs of the parent aziridines. The rates of ring closure in aqueous solution at pH approximately 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I approximately Br greater than Cl much greater than F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X- (X = Cl, Br) with aqueous HCO3- ions gives 3-[2-hyroxy-3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone. The activities of these prodrugs as radiosensitizers or as bioreductively activated cytotoxins were consistent with the proportion converted to the parent aziridine during the course of the experiment. alpha-[[(2-Bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1- ethanol (RB 6145, 10), the prodrug of alpha-[(1-aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanol (RSU-1069, 3), is identified as the most useful compound in terms of biological activity and rate of ring closure under physiological conditions.
通式为ImCH2CH(OH)CH2NCR1R2CR3R4的α-[(1-氮丙啶基)甲基]-2-硝基-1H-咪唑-1-乙醇（其中Im = 2-硝基咪唑，R1、R2、R3、R4 = H、Me）在体外和体内均为放射增敏剂以及对缺氧肿瘤细胞具有选择性生物还原激活作用的细胞毒素。在丙酮或丙酮水溶液中用卤化氢处理氮丙啶，得到通式为ImCH2CH(OH)CH2(+)-NH2CR1R2CR3R4X X-的相应2-卤乙胺（其中R1、R2、R3、R4 = H、Me，X = F、Cl、Br、I）。这些2-卤乙胺被评估为母体氮丙啶的前药。发现在pH约为6的水溶液中，闭环速率随甲基取代度的增加而增加，并且取决于离去基团的性质（I＞Br＞Cl＞＞F）。ImCH2CH(OH)CH2+NH2CH2CH2X X-（X = Cl、Br）与HCO3-水溶液的竞争反应生成3-[2-羟基-3-(2-硝基-1H-咪唑-1-基)丙基]-2-恶唑烷酮。这些前药作为放射增敏剂或生物还原激活细胞毒素的活性与实验过程中转化为母体氮丙啶的比例一致。α-[[(2-溴乙基)氨基]甲基]-2-硝基-1H-咪唑-1-乙醇（RB 6145，10），即α-[(1-氮丙啶基)甲基]-2-硝基-1H-咪唑-1-乙醇（RSU-1069，3）的前药，就生理条件下的生物活性和闭环速率而言，被确定为最有用的化合物。
