HYPOXIA-SELECTIVE ANTITUMOR AGENTS .8. BIS(NITROIMIDAZOLYL)ALKANECARBOXAMIDES - A NEW CLASS OF HYPOXIA-SELECTIVE CYTOTOXINS AND HYPOXIC CELL RADIOSENSITIZERS
HYPOXIA-SELECTIVE ANTITUMOR AGENTS .8. BIS(NITROIMIDAZOLYL)ALKANECARBOXAMIDES - A NEW CLASS OF HYPOXIA-SELECTIVE CYTOTOXINS AND HYPOXIC CELL RADIOSENSITIZERS
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DOI：
10.1021/jm00029a010
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发表时间：
1994-02-04
影响因子：
7.3
通讯作者：
DENNY, WA
中科院分区：
文献类型：
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作者：
HAY, MP;WILSON, WR;DENNY, WA
合成了一系列新型双(硝基咪唑基)烷基甲酰胺类化合物，并对其体外和体内低氧选择性细胞毒性和低氧细胞辐射增敏作用进行了评价。这些化合物是由预制的侧链酸组分和胺组分在室温下用磷氰酸二乙酯直接偶联而成。尽管这些化合物被设计为DNA交联剂的双生物还原前药，但没有一种化合物显示出DNA交联剂的活性，对缺乏和擅长修复交联物的细胞系具有同样的效力。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)在修复熟练的中国仓鼠细胞系a8中表现出高的低氧选择性细胞毒素(作用数小时后增加200倍)。对于烷基化的2-硝基咪唑(4；Rb 6145)(40倍)或简单的单硝基咪唑(5-25倍)，这种选择性比观察到的要大。双(硝基咪唑)类化合物的低水溶解度限制了对其低氧选择性的构效关系的研究，但两个硝基咪唑单元的最小分离度(大于5个原子)似乎是可取的。所有化合物在体外对低氧细胞都有放射增敏作用，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。当多个药物剂量与单剂量辐射联合使用时，化合物10在KHT肿瘤中引起额外的细胞杀伤。目前尚不清楚这种活性是否反映了低氧细胞的放射增敏或对低氧细胞的细胞毒性，但这种新的双生物还原剂显然值得进一步研究。
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 crosslinking activity, being equally potent against cell lines deficient and proficient in repair of crosslinks. 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.