Antineoplastic Agents. 605. Isoquinstatins

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.