Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons.
Synthesis of cytotoxic indenoisoquinoline topoisomerase I poisons.
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DOI：
10.1002/chin.199923176
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发表时间：
1999-01
影响因子：
7.3
通讯作者：
D. Strumberg;Y. Pommier;K. Paull;M. Jayaraman;P. Nagafuji;M. Cushman
中科院分区：
文献类型：
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作者：
D. Strumberg;Y. Pommier;K. Paull;M. Jayaraman;P. Nagafuji;M. Cushman
制备了许多茚并异喹啉并评价其在人癌细胞培养物中的细胞毒性和相对于拓扑异构酶1（top1）的活性。两种最具细胞毒性的茚并异喹啉被证明是顺式-6-乙基-5，6，12，13-四氢-2，3-二甲氧基-8，9-二氢吲哚。（亚甲二氧基）-5，11-二氧代-11H-茚并[1，2-c]异喹啉（21）和顺式-6-烯丙基-5，6，1,2，13-四氢-2，3-二甲氧基-8，9-二氢-1H-茚并[1，2-c]异喹啉（22）（亚甲二氧基）-5，11-二氧代-11H-茚并[1，2-c]异喹啉（22），当在55个人癌细胞培养物中测试时，两者均显示亚微摩尔平均图中点。两种最有效的top1抑制剂是6-（3-羧基-1-丙基）-5，6-二氢-5，11-二氧代-11H-茚并[1，2-c]异喹啉（26）和6-乙基-2，3-二甲氧基-8，9-（亚甲二氧基）-11H-茚并[1，2-c]异喹啉氯化物（27），这两种抑制剂也抑制top2，解绕DNA，并被认为是DNA嵌入剂。然而，另外两种有效的top1抑制剂，6-烯丙基-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（13 c）和5，6-二氢-6-（4-羟基丁-1-基）-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（19 a），不解旋DNA，也不影响top2。在茚并异喹啉存在下检测到的一些DNA切割位点与用喜树碱观察到的那些不同。由茚并异喹啉诱导的切割位点被盐处理逆转，这与茚并异喹啉对top1可切割复合物的可逆捕获一致。一般来说，茚并异喹啉类药物作为top1抑制剂的效力与其作为细胞毒性药物的效力无关，因为一些最具细胞毒性的药物对top1几乎没有影响。另一方面，与top1相比，最有效的茚并异喹啉并不是最具细胞毒性的。在几种情况下，观察到细胞毒性和活性相对于top1的中等活性。
A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs topoisomerase 1 (top1). The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (21) and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (22), both of which displayed submicromolar mean graph midpoints when tested in 55 human cancer cell cultures. Two of the most potent top1 inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5, 11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2, 3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27), both of which also inhibited top2, unwound DNA, and are assumed to be DNA intercalators. However, two additional potent top1 inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8, 9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect top2. Some of the DNA cleavage sites detected in the presence of the indenoisoquinolines were different from those seen with the camptothecins. The cleavage sites induced by the indenoisoquinolines were reversed by salt treatment, which is consistent with the reversible trapping of top1 cleavable complexes by the indenoisoquinolines. In general, the potencies of the indenoisoquinolines as top1 inhibitors did not correlate with their potencies as cytotoxic agents, as some of the most cytotoxic agents had little if any effect on top1. On the other hand, the most potent of the indenoisoquinolines vs top1 were not the most cytotoxic. In several cases, moderate activity was observed for both cytotoxicity and activity vs top1.