Hay M P, Wilson W R, Moselen J W, Palmer B D, Denny W A
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
J Med Chem. 1994 Feb 4;37(3):381-91. doi: 10.1021/jm00029a010.
A series of novel bis(nitroimidazolyl)alkanecarboxamides has been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitisation in vitro and in vivo. The compounds were prepared by direct coupling of preformed side chain acid and amine components, using diethyl phosphorocyanidate at room temperature. Although designed to be bis-bioreductive prodrugs of DNA cross-linking agents, none of the compounds showed evidence of DNA cross-linking activity, being equally potent against cell lines deficient and proficient in repair of cross-links. However, one of these compounds, N-[2-(2-methyl-5-nitro-1H-imidazolyl)ethyl]-4-(2-nitro-1H- imidazolyl)butanamide (10; SN 24699), showed high hypoxic selectivity as a cytotoxin (rising to 200-fold after exposure to the drug for several hours) in the repair-proficient Chinese hamster cell line AA8. This selectivity was greater than observed for the alkylating 2-nitroimidazole (4; RB 6145) (40-fold) or simple mononitroimidazoles (5-25-fold). Investigation of structure-activity relationships for hypoxic selectivity of bis(nitroimidazoles) was restricted by their low aqueous solubility, but a certain minimum separation of the two nitroimidazole units (by more than five atoms) appears desirable. All the compounds radiosensitized hypoxic cells in vitro but were little more potent as radiosensitizers than the corresponding monomeric nitroimidazoles. Compound 10 caused additional cell killing in the KHT tumor when multiple drug doses were administered in combination with a single dose of radiation. It is not yet clear whether this activity reflects hypoxic cell radiosensitization or cytotoxicity toward hypoxic cells, but this new class of bis-bioreductive agent clearly warrants further investigation.
已制备了一系列新型双（硝基咪唑基）烷烃羧酰胺，并在体外和体内对其进行了缺氧选择性细胞毒性和缺氧细胞放射增敏作用的评估。这些化合物是通过在室温下使用氰基磷酸二乙酯将预先形成的侧链酸和胺组分直接偶联制备的。尽管设计为DNA交联剂的双生物还原前药，但这些化合物均未显示出DNA交联活性的证据，对交联修复缺陷和 proficient 的细胞系具有同等效力。然而，其中一种化合物N-[2-(2-甲基-5-硝基-1H-咪唑基)乙基]-4-(2-硝基-1H-咪唑基)丁酰胺（10；SN 24699）在修复 proficient 的中国仓鼠细胞系AA8中显示出作为细胞毒素的高缺氧选择性（暴露于药物数小时后增加至200倍）。这种选择性大于烷基化的2-硝基咪唑（4；RB 6145）（40倍）或简单的单硝基咪唑（5-25倍）所观察到的选择性。双（硝基咪唑）缺氧选择性的构效关系研究受到其低水溶性的限制，但两个硝基咪唑单元之间一定的最小间隔（超过五个原子）似乎是理想的。所有化合物在体外均能使缺氧细胞放射增敏，但作为放射增敏剂的效力并不比相应的单体硝基咪唑强多少。当与单剂量辐射联合给予多个药物剂量时，化合物10在KHT肿瘤中引起了额外的细胞杀伤。目前尚不清楚这种活性是反映缺氧细胞放射增敏作用还是对缺氧细胞的细胞毒性，但这类新型双生物还原剂显然值得进一步研究。
