Design, synthesis and biological evaluation of novel artesunate-selenylindole hybrids against colorectal cancer.

Colorectal cancer (CRC) remains a major global public health threat, creating an urgent demand for novel therapeutic agents. Artesunate (ART), a semisynthetic derivative of artemisinin, has demonstrated anti-colorectal cancer effects, but its moderate antitumor potency (IC50 > 50 μM) severely limits further clinical application. To enhance the activity against colorectal cancer (CRC), we adopted a scaffold hybridization strategy to rationally design and synthesize 22 novel artesunate-selenylindole hybrids. All derivatives were screened for their anti-proliferative activity against four human colorectal cancer cell lines (HT29, HCT116, SW480, SW620) and normal human liver cells (LO2). Most derivatives exhibited superior anti-proliferative activity compared to ART (IC50 > 50 μM), and compound 3e demonstrated significant anti-proliferative activity against HCT-116 cells with an IC50 of 6.0 μM and exhibiting no toxicity toward normal cells. Further cellular assays verified that 3e suppresses colony formation and cell migration of HCT116 in a dose-dependent fashion. Mechanistically, 3e inhibits TrxR activity to trigger intracellular ROS overaccumulation and mitochondrial dysfunction. The accumulated oxidative stress elicits G0/G1 cell-cycle arrest and pronounced mitochondrial-dependent apoptosis, characterized by elevated Bax, cleaved-caspase-3, cleaved-PARP, reduced Bcl-2 and procaspase-3, and the release of cytochrome-c from mitochondria to cytoplasm. In summary, compound 3e displays potent anti-CRC effects through TrxR/ROS-driven oxidative-stress signaling, representing an attractive lead scaffold for anti-CRC drug discovery.