Philipova Irena, Atanasova Mariyana, Mihaylova Rositsa, Dailova-Barzeva Asine, Ivanov Stefan M, Simeonova Rumyana L, Stavrakov Georgi
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bontchev Str. Bl. 9, 1113 Sofia, Bulgaria.
Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria.
Molecules. 2025 Jul 24;30(15):3101. doi: 10.3390/molecules30153101.
Ferrocene (Fc), a redox-active organometallic scaffold, has attracted significant attention in medicinal chemistry due to its favorable physicochemical and pharmacological properties. The present study explores the therapeutic potential of novel Fc-functionalized analogues of imatinib and nilotinib, aimed at targeting BCR-ABL1+ chronic myeloid leukemia (CML) cells. A series of Fc-based derivatives (compounds , , , and ) were synthesized by systematically substituting key pharmacophoric regions of the parent tyrosine kinase inhibitors with Fc units. The antiproliferative activity of these compounds was evaluated against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, and LAMA-84), with imatinib serving as a reference drug. Biological assays revealed distinct structure-activity relationships. Compounds and demonstrated superior activity against the K-562 cell line, while compounds and exhibited enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib. Selectivity assays further indicated favorable toxicity profiles of compounds and toward malignant versus non-malignant cells. Molecular docking studies supported these findings, showing that Fc substitution alters binding interactions within the c-Abl kinase ATP-binding site while retaining key stabilizing contacts. Computationally predicted LEs showed strong correlation with experimental data, especially for K-562 and LAMA-84 cells, confirming the kinase as a relevant target.
二茂铁（Fc）是一种具有氧化还原活性的有机金属支架，因其良好的物理化学和药理特性，在药物化学领域备受关注。本研究探索了新型二茂铁功能化的伊马替尼和尼洛替尼类似物的治疗潜力，旨在靶向BCR-ABL1+慢性髓性白血病（CML）细胞。通过用二茂铁单元系统取代母体酪氨酸激酶抑制剂的关键药效基团区域，合成了一系列基于二茂铁的衍生物（化合物、、、和）。以伊马替尼作为参考药物，评估了这些化合物对四种BCR-ABL1阳性白血病细胞系（K-562、BV-173、AR-230和LAMA-84）的抗增殖活性。生物学试验揭示了不同的构效关系。化合物和对K-562细胞系表现出优异的活性，而化合物和与伊马替尼相比，对BV-173和AR-230细胞表现出更强的效力和更高的配体效率（LEs）。选择性试验进一步表明化合物和对恶性细胞与非恶性细胞具有良好的毒性特征。分子对接研究支持了这些发现，表明二茂铁取代改变了c-Abl激酶ATP结合位点内的结合相互作用，同时保留了关键的稳定接触。计算预测的LEs与实验数据显示出强烈的相关性，尤其是对K-562和LAMA-84细胞，证实该激酶是一个相关靶点。
