Discovery of Indolo[3,2-c]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-c]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds 23 and 31 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 23 and 31 possessed good oral safety profiles. In xenograft models, compound 23 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 23 as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.

Discovery of novel itaconimide-based derivatives as potent HDAC inhibitors for the efficient treatment of prostate cancer.

Histone deacetylases (HDACs) are a family of enzymes that play important roles in the development and progression of cancers. Inhibition of HDACs has been widely studied as a therapeutic strategy in the development of anticancer drugs. However, developing HDAC inhibitors that are effective for solid tumors remains a great challenge. In this work, we designed and synthesized a series of itaconimide-based derivatives as potent HDAC inhibitors. Among them, compound 17q exhibited potent inhibition of HDAC1/2/3/6, with good antiproliferative activity in vitro and an excellent pharmacokinetic profile. Compound 17q significantly inhibited tumor growth in a DU145 xenograft tumor model and showed no obvious toxicity. Moreover, when 17q was combined with other prostate cancer therapeutics, outstanding synergistic effects were observed and the toxic side effects of DTX were reduced. Overall, based on the data, these inhibitors may offer promising new targeted therapies for prostate cancer.