Design, Synthesis, In Vitro Evaluation of Antitumor Activity, and Molecular Docking Studies of D‐ring‐opened Indazole‐Matrine Derivatives as Potential Anticancer Agents

To develop matrine derivatives with improved anticancer activity, we designed and synthesized 16 derivatives using matrine as the lead compound through drug splicing principles. Using the MTT assay, we evaluated their antiproliferative effects against three human cancer cell lines: cervical cancer (HeLa), hepatocellular carcinoma (Huh-7), and triple-negative breast cancer (MDA-MB-231). Most compounds demonstrated superior activity to matrine, with W12 showing the strongest effects (IC₅₀ values: 4.8 ± 0.33 µM for Huh-7, 8.03 ± 1.28 µM for MDA-MB-231, and 10.11 ± 0.39 µM for HeLa). W12 induced concentration-dependent morphological changes, G1 phase cell cycle arrest, apoptosis, and inhibited colony formation and migration. Molecular docking revealed that W12 forms hydrogen bonds and other interactions with TRK-related protein 5KVT. These findings suggest that W12 is a promising anticancer drug precursor.