Novel 1,1′-Desymmetrized Ferrocene Conjugates of Imatinib and Nilotinib: Synthesis, Cytotoxic Activity and Molecular Docking Studies

The incorporation of ferrocene into established pharmacophores represents a promising strategy for combining targeted activity with the properties of the organometallic scaffold. Building on our previous work on ferrocene-modified tyrosine kinase inhibitors (TKIs), this study presents the synthesis, biological evaluation and molecular docking analysis of four novel 1,1′-desymmetrized ferrocenyl derivatives of imatinib and nilotinib, designed to investigate how subtle structural modifications of the ferrocenyl moiety influence their cytotoxic activity and predicted interactions with the ABL1 kinase domain. The imatinib-derived compounds 5 and 6 contain amino and acetamido substituents, respectively, whereas the nilotinib-derived compounds 16 and 17 incorporate acetyl and benzoyl functionalities. Their cytotoxic activity was evaluated against four BCR::ABL1-positive leukemia cell lines with distinct molecular characteristics (BV-173, K-562, AR-230, and LAMA-84), with non-malignant CCL-1 fibroblasts included for assessment of selectivity and imatinib used as a reference drug. All four derivatives exhibited cytotoxic activity, with pronounced structure- and cell line-dependent differences. Compound 5 showed the most favorable activity profile, with pronounced cytotoxicity against AR-230 cells and activity comparable to or greater than imatinib in BV-173 and K-562 cells. In contrast, compound 17 was the most active derivative in LAMA-84 cells and exhibited the highest selectivity among all analogues in the series across the entire leukemia panel. Molecular docking indicated that ferrocenyl incorporation altered the binding orientation within the ABL1 kinase domain, while compound 5 showed the smallest positional deviation, consistent with its favorable cytotoxic profile. The results demonstrate that additional functionalization of the ferrocenyl moiety produces cell-line-dependent changes in cytotoxic activity without consistently improving potency or selectivity compared with previously reported monosubstituted analogues. Nevertheless, the successful synthesis of 1,1′-desymmetrized ferrocene conjugates provides new opportunities for structural diversification and further optimization of this class of compounds.