Imatinib-Based Derivative: Synthesis, Computational Modeling, and Experimental Anticancer Activity

Cancer remains one of the major causes of death worldwide. Tyrosine kinase inhibitors (TKIs) represent an important class of targeted anticancer agents because they block key oncogenic signaling pathways. Imatinib mesylate was among the first TKIs introduced in clinical oncology and has significantly improved the treatment of several malignancies. Nevertheless, its clinical use is associated with adverse effects, which highlights the need to develop modified derivatives with improved efficacy and reduced toxicity.

In the present work, a new compound, imatinib aescinate, was prepared by dissolving imatinib and aescin separately in ethyl alcohol and combining the solutions under continuous stirring, followed by filtration and acetone-induced precipitation. For identification and structural characterization, the compound was analyzed using UV and FTIR spectroscopy, scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS), X-ray diffraction (XRD), thermogravimetric-differential thermal analysis (TGA/DTA), and HPLC. Antiproliferative activity was assessed in MCF-7 breast cancer cells using a CCK-8 cell viability assay (24 h), and wound closure was evaluated using a scratch assay. To understand potential molecular interactions, molecular dynamics simulations together with MM-PBSA binding energy calculations were also performed.

The synthesized compound exhibited greater antiproliferative activity against MCF-7 cells than either imatinib mesylate or aescin alone. The IC50 values determined from a 24 h CCK-8 assay were: imatinib aescinate 15.16 μM, aescin alone 23.55 μM, and imatinib mesylate 76.66 μM. Imatinib aescinate also inhibited MCF-7 wound closure in a concentration-dependent manner in the scratch assay. Computational analysis indicated stable binding of imatinib aescinate to the BCR-ABL tyrosine kinase (PDB ID: 2HYY). Molecular dynamics simulations suggested reduced conformational flexibility of the protein-ligand complex, and MM-PBSA calculations supported favorable binding energy.

Imatinib aescinate was approximately fivefold more potent than imatinib mesylate and 1.6-fold more potent than aescin, indicating enhanced antiproliferative activity. Its concentration-dependent inhibition of wound closure also suggests potential antimigratory effects, although reduced cell proliferation may contribute to this result. Computational findings supported stable and favorable binding to BCR-ABL; however, the underlying mechanism requires experimental confirmation. Further studies should evaluate kinase inhibition, toxicity, and in vivo efficacy.

Overall, the results indicate that imatinib aescinate shows enhanced antiproliferative activity against MCF-7 cells compared with its individual components. Computational predictions suggest that the compound may interact with kinase targets; however, direct biochemical validation is required before definitive mechanistic conclusions can be drawn. These findings identify imatinib aescinate as a promising candidate for further preclinical investigation as a potential anticancer agent.