Discovery and optimization of indirubin derivatives as novel ferroptosis inducers for the treatment of colon cancer.

Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC50 = 0.49 ± 0.02 µM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer.

New N-oxide alkaloids from the stems of Sinomenium acutum.

Six new alkaloids (1-6) and six known alkaloids (7-12) were obtained from the stems of Sinomenium acutum. Among them, compounds 1-3 and 6 were four N-oxide alkaloids. The structures and absolute configurations of these new alkaloids were elucidated through comprehensive data of 1D and 2D NMR, HRESIMS and ECD spectra. All isolated compounds were evaluated in vitro for their inhibitory activities against nitric oxide (NO) production and inhibitory effects on AChE. Among them, the sinomenine N-oxide (9) was the most potent NO production inhibitor, with an IC50 value of 23.04 µM.