Cushman M, Jayaraman M, Vroman J A, Fukunaga A K, Fox B M, Kohlhagen G, Strumberg D, Pommier Y
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2000 Oct 5;43(20):3688-98. doi: 10.1021/jm000029d.
In an attempt to design and synthesize potential anticancer agents acting by inhibition of topoisomerase I (top1), a new series of indenoisoquinolines was prepared and tested for cytotoxicity in human cancer cell cultures and for activity against top1. The synthesis relied on the condensation of substituted Schiff bases with homophthalic anhydrides to produce cis-3-aryl-4-carboxyisoquinolones that were cyclized to indenoisoquinolines in the presence of thionyl chloride. Both top1 inhibitory activity and cytotoxicity maximized in a single compound, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline hydrochloride (19a), which proved to be a very potent top1 inhibitor having a 110 nM mean graph midpoint (MGM) when tested for cytotoxicity in 55 human cancer cell cultures. A number of structurally related indenoisoquinolines were also obtained that had both potent cytotoxicity as well as top1 inhibitory activity. The key feature of the more potent compounds was the presence of an aminoalkyl side chain on the indenoisoquinoline nitrogen atom. The DNA cleavage patterns induced by top1 in the presence of the indenoisoquinolines were different from those seen with camptothecin. Some of the cleavage sites induced by the indenoisoquinolines were different from those seen with camptothecin, and conversely, camptothecin induced unique cleavage sites not apparent with the indenoisoquinolines. However, both camptothecin and the indenoisoquinolines also induced DNA cleavage sites that were the same in both series but varied in intensity. In addition, some of the DNA cleavages seen with the free base of 19a (compound 18c) in the presence of top1 were inhibited at higher drug concentrations, suggesting either a direct inhibition of the enzyme or an alternative mechanism involving DNA intercalation. Consistent with intercalation, compound 18c did unwind DNA.
为了设计和合成通过抑制拓扑异构酶I（top1）发挥作用的潜在抗癌药物，制备了一系列新的茚并异喹啉，并在人癌细胞培养物中测试其细胞毒性以及对top1的活性。合成过程依赖于取代席夫碱与高邻苯二甲酸酐的缩合反应，以生成顺式-3-芳基-4-羧基异喹啉酮，后者在亚硫酰氯存在下环化生成茚并异喹啉。top1抑制活性和细胞毒性在单一化合物6-[3-(2-羟乙基)氨基丙基]-5,6-二氢-2,3-二甲氧基-8,9-亚甲二氧基-5,11-二氧代-11H-茚并[1,2-c]异喹啉盐酸盐（19a）中达到最大值，在55种人癌细胞培养物中测试细胞毒性时，该化合物被证明是一种非常有效的top1抑制剂，平均图形中点（MGM）为110 nM。还获得了许多结构相关的茚并异喹啉，它们兼具强大的细胞毒性和top1抑制活性。更有效化合物的关键特征是茚并异喹啉氮原子上存在氨基烷基侧链。茚并异喹啉存在时top1诱导的DNA切割模式与喜树碱诱导的不同。茚并异喹啉诱导的一些切割位点与喜树碱诱导的不同，相反，喜树碱诱导的独特切割位点在茚并异喹啉处理时不明显。然而，喜树碱和茚并异喹啉都诱导了两个系列中相同但强度不同的DNA切割位点。此外，在top1存在下，19a游离碱（化合物18c）出现的一些DNA切割在较高药物浓度下受到抑制，这表明要么是对该酶的直接抑制，要么是涉及DNA嵌入的另一种机制。与嵌入作用一致，化合物18c确实能使DNA解旋。
