硝基苯并环磷酰胺化合物的还原及其细胞增殖抑制活性的研究

The study on reduction and antiproliferation activity of nitrobenzocyclophosphamidesin cell culture

目的对以基因导向酶前药治疗策略为目的所合成的硝基环磷酰胺类化合物还原性及细胞增殖抑制作用进行研究。方法以NaBH4化学还原和E .coli硝基还原酶进行还原性研究;以E .coli硝基还原酶(T116 )和人醌氧化还原酶(NQO1F179)表达细胞(V79)进行细胞增殖抑制作用研究。结果以氧原子与硝基苯环相连的环磷酰6b和6d对E .coli硝基还原酶表达细胞增殖毒性的选择性在30倍以上。

PurposeTo make efforts to obtain potential anticancer prodrugs for gene-directed enzyme prodrug therapy using E.coli nitroreductase.MethodsThe reductive activation and antiproliferative activity in cell culture of four benzocyclophosphamides 6a-d were tested.Results6b and 6d,both with a benzylic oxygen in the phosphorinane ring para to the nitro group,showed a modest 30 fold enhanced cyctotoxicity in E. coli nitroreductase-expressing cells.ConclusionThese results suggest that compounds 6b and 6d represent a new structure protype for reduction and a lead for further modification in the development of better analogues with improved selective toxicity to be used in gene-directed enzyme prodrug therapy.