Braña M F, Castellano J M, Morán M, Emling F, Kluge M, Schlick E, Klebe G, Walker N
Knoll S.A., Madrid, Spain.
Arzneimittelforschung. 1995 Dec;45(12):1311-8.
New benz[d,e]isoquinoline-1,3-diones related to mitonafide (CAS 54824-17-8) and amonafide (CAS 69408-81-7) with double substitution on the chromophore and branched side chains have been synthesized and their biological activity determined. Molecular modeling studies of 3a based on X-ray crystallographic data of mitonafide have shown that the aromatic system intercalates between GC steps of DNA. The in vitro cytotoxic test data using CX-1 and LX-1 cells showed higher cytotoxic activities in disubstituted derivatives compared to both lead compounds. Some of the compounds have been selected for in vivo test using L1210 tumor cells and CX-1 cells. Two of them (3b and 3j) have shown promising activity as good candidates for clinical development.
已合成了与米托萘腙（CAS 54824-17-8）和氨萘非特（CAS 69408-81-7）相关的、发色团具有双取代且带有支链侧链的新型苯并[d,e]异喹啉-1,3-二酮，并测定了它们的生物活性。基于米托萘腙的X射线晶体学数据对3a进行的分子模拟研究表明，芳香体系插入DNA的GC碱基对之间。使用CX-1和LX-1细胞的体外细胞毒性试验数据显示，与两种先导化合物相比，双取代衍生物具有更高的细胞毒性活性。已选择一些化合物用于使用L1210肿瘤细胞和CX-1细胞的体内试验。其中两种化合物（3b和3j）作为临床开发的良好候选物显示出有前景的活性。
