Chen Q, Deady L W, Baguley B C, Denny W A
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
J Med Chem. 1994 Mar 4;37(5):593-7. doi: 10.1021/jm00031a008.
A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake.
合成了一系列药物N-[2-(二甲氨基)乙基]-吖啶-4-甲酰胺（DACA，目前正处于临床试验阶段）的氮杂吖啶（苯并萘啶）类似物。通过荧光乙锭置换试验测定，这些化合物显示出与DACA相似的DNA结合亲和力，但在体外对P388白血病细胞的细胞毒性通常较弱。唯一显示出比DACA更高细胞毒性的化合物是在（吖啶）1位带有硝基取代基的类似物；与1-硝基吖啶硝吖啶类似，这些化合物可能会进行还原代谢。唯一显示出显著体内抗白血病活性的氮杂吖啶是苯并[b][1,5]萘啶-6-甲酰胺。这些化合物活性出乎意料地低（考虑到DACA中取代基的广泛可接受性）的一个可能原因可能是它们的亲脂性低得多，这可能导致细胞摄取率较低。
