Synthesis, Anti‐tumor Evaluation and Mechanism Study of Indolinone‐Pyrimidine Derivatives Against Chronic Myeloid Leukemia Cells

ABSTRACT Molecular hybridization represents a well‐established strategy for anticancer drug discovery. Herein, we report the design and synthesis of 22 novel indolinone‐pyrimidine hybrids generated by introducing a pyrimidine fragment at the C‐5 position of the indolinone core. All synthesized compounds were evaluated for their in vitro antiproliferative activity against a panel of four human cancer cell lines (K562, A549, PC‐3, and 5637). Among these, compound D14 emerged as a promising hit, exhibiting moderate activity against chronic myeloid leukemia K562 cells with an IC 50 value of 8.10 ± 0.33 µM. Preliminary mechanistic studies revealed that D14 exerts its anti‐leukemic effect primarily through induction of apoptosis, an effect potentially associated with elevated reactive oxygen species (ROS) levels, G0/G1 phase cell cycle arrest, and activation of the Hippo signaling pathway. Molecular docking studies offered a putative binding mode of D14 within the ATP‐binding pocket of BCR‐ABL1 kinase, suggesting key interactions with active‐site residues. Collectively, these findings position D14 as a promising lead for further structural optimization and highlight a new direction for the development of indolinone‐based anti‐leukemia therapeutics.