Discovery of Indolo[3,2-]isoquinoline Derivatives as Novel Top1/2 Dual Inhibitors with Orally Efficacious Antitumor Activity and Low Toxicity.

Topoisomerase (Top) inhibitors used in clinical cancer treatments are limited because of their toxicity and severe side effects. Noteworthily, Top1/2 dual inhibitors overcome the compensatory effect between Top1 and 2 inhibitors to exhibit stronger antitumor efficacies. In this study, a series of indolo[3,2-]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds and with increasing reactive oxygen species levels damage DNA, inducing both cancer cell apoptosis and cycle arrest. Importantly, the results of the toxicity studies showed that compounds and possessed good oral safety profiles. In xenograft models, compound exhibited remarkable antitumor potency, which was superior to the clinical Top inhibitors irinotecan and etoposide. Overall, this work highlights the therapeutic potential and safety profile of compound as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.