Naylor M A
Department of Medicinal Chemistry, MRC Radiobiology Unit, Chilton, Oxon, UK.
Oncol Res. 1994;6(10-11):483-91.
A series of imidazo [1,2-a] quinoxaline mono-N-oxides and their aza- analogues have been synthesized together with analogues substituted in the 8-position. These compounds have been evaluated as bioreductively activated cytotoxins in vitro and in vivo. These compounds had differential cytotoxicities in vitro of up to 20 for 8-amino derivatives such as RB90740 and 65 for 8-aminoalkoxy derivatives such as 1,2-dihydro-8-(1-(demethylamino)ethoxy)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide, but were disappointing in vivo with a maximum growth delay of 10 days compared with 30 days for SR4233 in the RIF-1 tumor model. RB90740 is only effective at killing V79 cells at extremely low levels of oxygen, in contrast to SR4233, and this oxygen dependence can explain the poor and often variable activity of the compound in vivo. 1,2-dihydro-8-(1-(demethylamino)ethoxy)-4-phenylmidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide, as the most effective drug in vitro, remains the lead structure for any further drug development.
一系列咪唑并[1,2 - a]喹喔啉单 - N - 氧化物及其氮杂类似物以及在8位有取代基的类似物已被合成。这些化合物已在体外和体内作为生物还原激活的细胞毒素进行了评估。这些化合物在体外具有不同的细胞毒性，对于8 - 氨基衍生物如RB90740，细胞毒性高达20；对于8 - 氨基烷氧基衍生物如1,2 - 二氢 - 8 - (1 - (去甲基氨基)乙氧基)-4 - 苯基咪唑并[1,2 - a]吡啶并[3,2 - e]吡嗪5 - 氧化物，细胞毒性高达65。但在体内表现不佳，在RIF - 1肿瘤模型中，与SR4233的30天最大生长延迟相比，其最大生长延迟为10天。与SR4233相反，RB90740仅在极低氧水平下对V79细胞有效，这种对氧的依赖性可以解释该化合物在体内活性不佳且常常变化的原因。1,2 - 二氢 - 8 - (1 - (去甲基氨基)乙氧基)-4 - 苯基咪唑并[1,2 - a]吡啶并[3,2 - e]吡嗪5 - 氧化物作为体外最有效的药物，仍然是任何进一步药物开发的先导结构。
