In order to further explore quinoline-type structural modification of the powerful anticancer drug dolastatin 10, an Indian Ocean sea hare constituent and parent molecule of the very successful antibody drug conjugate (ADC) Adcetris, our recent quinstatin study has been extended by replacing the quinoline ring with an isoquinoline. The resulting isoquinstatins (4–6) were modified to N-terminal desmethylisoquinstatins (7–9) and, in turn, bonded to appropriate linker units to give linker-desmethylisoquinstatin conjugates 11–13 in preparation for eventual monoclonal antibody attachment. Comparison of the new isoquinstatins with their quinstatin counterparts against six human cancer cell lines indicated the isoquinstatins to have GI₅₀ values that were comparable to or somewhat higher than those of the isomeric quinstatins. However, desmethylisoquinstatin 5 (7) was significantly more potent than its desmethylquinstatin 5 analogue. When evaluated against quinstatin 8, its isoquinstatin 8 (6) counterpart was somewhat less potent. In general, the isoquinstatins evaluated proved to be quite strong cancer cell growth inhibitors.

中文翻译：

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抗肿瘤药。605.异喹他汀

为了进一步探索功能强大的抗癌药dolastatin 10（一种非常成功的抗体药物偶联物（ADC）Adcetris的印度洋海兔成分和母体分子）的喹啉型结构修饰，我们最近的quinstatin研究已通过替换喹啉来扩展与异喹啉环。将得到的异喹他汀类药物（4 – 6）修饰为N-末端去甲基异喹他汀类药物（7 – 9），然后与适当的接头单元键合，得到接头－去甲基异喹他汀类药物缀合物11 – 13为最终的单克隆抗体附着做准备。将新的异喹他汀与它们的喹他丁素对应物与六种人类癌细胞系进行比较后发现，异喹他汀的GI ₅₀值可与同分异构的喹他汀相比或更高。然而，去甲基异喹他汀5（7）比其去甲基喹他汀5类似物更有效。当针对喹他汀8评估时，其异喹他汀8（6）对应物效力稍差。通常，所评估的异喹他汀被证明是相当强的癌细胞生长抑制剂。