Sami S M, Dorr R T, Sólyom A M, Alberts D S, Remers W A
Department of Pharmacology/Toxicology, University of Arizona, Tucson 85721.
J Med Chem. 1995 Mar 17;38(6):983-93. doi: 10.1021/jm00006a018.
Sets of 2-[2-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (delta Tm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.
以适当取代的蒽为原料，合成了蒽核上八个位置各带有氨基和乙酰氨基的2-[2-(二甲氨基)乙基]-1,2-二氢-3H-二苯并[de,h]异喹啉-1,3-二酮系列化合物。它们在体外抗肿瘤和心脏毒性试验中的评估结果显示，其效力强烈依赖于取代位置。某些化合物，包括4-、5-、7-和9-氨基衍生物，显示出比未取代的母体化合物偶氮萘非更高的效力。其中，7-氨基偶氮萘非相对于细胞毒性具有较低的心脏毒性。总体而言，乙酰氨基类似物对肿瘤细胞和新生大鼠心脏心肌细胞的效力低于氨基衍生物；然而，5-(乙酰氨基)偶氮萘非具有高度心脏毒性。9-氨基偶氮萘非在小鼠体内对P388白血病的疗效比偶氮萘非或氨萘非更好。氨基类似物提高DNA转变熔解温度（ΔTm）的能力与其对实体瘤、白血病细胞或心肌细胞的效力之间存在统计学上的显著相关性。
