{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:51:13Z","timestamp":1790351473213,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Fund, Bulgaria","award":["KP-06-N53\/9, 11.11.2021"],"award-info":[{"award-number":["KP-06-N53\/9, 11.11.2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 6, 9, 14, and 18) 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\u2013activity relationships. Compounds 6 and 9 demonstrated superior activity against the K-562 cell line, while compounds 14 and 18 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 9 and 14 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.<\/jats:p>","DOI":"10.3390\/molecules30153101","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T15:19:22Z","timestamp":1753370362000},"page":"3101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Design, Docking Analysis, and Structure\u2013Activity Relationship of Ferrocene-Modified Tyrosine Kinase Inhibitors: Insights into BCR-ABL Interactions"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1192-1094","authenticated-orcid":false,"given":"Irena","family":"Philipova","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bontchev Str. Bl. 9, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9761-0355","authenticated-orcid":false,"given":"Mariyana","family":"Atanasova","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-0730","authenticated-orcid":false,"given":"Rositsa","family":"Mihaylova","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asine","family":"Dailova-Barzeva","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6949-2328","authenticated-orcid":false,"given":"Stefan M.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4860-9053","authenticated-orcid":false,"given":"Rumyana L.","family":"Simeonova","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8893-0346","authenticated-orcid":false,"given":"Georgi","family":"Stavrakov","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bontchev Str. Bl. 9, 1113 Sofia, Bulgaria"},{"name":"Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1021\/ar00031a002","article-title":"Bioorganometallic Chemistry: A Future Direction for Transition Metal Organometallic Chemistry?","volume":"26","author":"Jaouen","year":"1993","journal-title":"Acc. Chem. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1021\/om0300777","article-title":"Bioorganometallic Chemistry: Structural Diversity of Organometallic Complexes with Bioligands and Molecular Recognition Studies of Several Supramolecular Hosts with Biomolecules, Alkali-Metal Ions, and Organometallic Pharmaceuticals","volume":"22","author":"Fish","year":"2003","journal-title":"Organometallics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1039\/B707077M","article-title":"Bioorganometallic Chemistry\u2014From Teaching Paradigms to Medicinal Applications","volume":"38","author":"Hartinger","year":"2009","journal-title":"Chem. Soc. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/aoc.1202","article-title":"On the Medicinal Chemistry of Ferrocene","volume":"21","author":"Fouda","year":"2007","journal-title":"Appl. Organomet. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"0066","DOI":"10.1038\/s41570-017-0066","article-title":"The Medicinal Chemistry of Ferrocene and Its Derivatives","volume":"1","author":"Patra","year":"2017","journal-title":"Nat. Rev. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5931","DOI":"10.1021\/cr0101510","article-title":"Bioorganometallic Chemistry of Ferrocene","volume":"104","year":"2004","journal-title":"Chem. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.1039\/C8DT03440K","article-title":"Ferrocene-Appended Pharmacophores: An Exciting Approach for Modulating the Biological Potential of Organic Scaffolds","volume":"48","author":"Singh","year":"2019","journal-title":"Dalton Trans."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8802","DOI":"10.1039\/C5CS00486A","article-title":"Ferrocifen Type Anti Cancer Drugs","volume":"44","author":"Jaouen","year":"2015","journal-title":"Chem. Soc. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Top, S., Tang, J., Vessi\u00e8res, A., Carrez, D., Provot, C., and Jaouen, G. (1996). Ferrocenyl Hydroxytamoxifen: A Prototype for a New Range of Oestradiol Receptor Site-Directed Cytotoxics. Chem. Commun., 955\u2013956.","DOI":"10.1039\/CC9960000955"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"716","DOI":"10.2533\/chimia.2007.716","article-title":"Ferrocifens and Ferrocifenols as New Potential Weapons against Breast Cancer","volume":"61","author":"Nguyen","year":"2007","journal-title":"Chimia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1021\/jm100020w","article-title":"Organometallic Anticancer Compounds","volume":"54","author":"Gasser","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/anie.200504604","article-title":"New Principles in Medicinal Organometallic Chemistry","volume":"45","author":"Schatzschneider","year":"2006","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jinorgbio.2009.12.020","article-title":"A Ferrocenyl Derivative of Hydroxytamoxifen Elicits an Estrogen Receptor-Independent Mechanism of Action in Breast Cancer Cell Lines","volume":"104","author":"Corbet","year":"2010","journal-title":"J. Inorg. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/s12276-020-0384-2","article-title":"ROS in Cancer Therapy: The Bright Side of the Moon","volume":"52","author":"Perillo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1021\/acs.organomet.0c00306","article-title":"Anticancer Effect of an Electronically Coupled Oligoferrocene","volume":"39","author":"Zeh","year":"2020","journal-title":"Organometallics"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"\u00d6zkan, H.G., and Mokhir, A. (2022). A Prodrug of 3-(Ferrocenylaminocarbonyloxymethyl)Phenol Activated by Reactive Oxygen Species in Cancer Cells. J. Inorg. Biochem., 233.","DOI":"10.1016\/j.jinorgbio.2022.111859"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"561","DOI":"10.2533\/chimia.2019.561","article-title":"Investigations into the Potential Role of Metabolites on the Anti-Leukemic Activity of Imatinib, Nilotinib and Midostaurin","volume":"73","author":"Manley","year":"2019","journal-title":"Chimia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1039\/D3MD00030C","article-title":"Ferrocene Modified Analogues of Imatinib and Nilotinib as Potent Anti-Cancer Agents","volume":"14","author":"Philipova","year":"2023","journal-title":"RSC Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1055\/s-2007-983754","article-title":"An Efficient Synthesis of Nilotinib (AMN107)","volume":"2007","author":"Huang","year":"2007","journal-title":"Synthesis"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Arter, C., Trask, L., Ward, S., Yeoh, S., and Bayliss, R. (2022). Structural Features of the Protein Kinase Domain and Targeted Binding by Small-Molecule Inhibitors. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.102247"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40880-016-0108-0","article-title":"The Philadelphia Chromosome in Leukemogenesis","volume":"35","author":"Kang","year":"2016","journal-title":"Chin. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3889","DOI":"10.1021\/jm400072p","article-title":"Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors","volume":"56","author":"Peng","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1107\/S0907444906047287","article-title":"Structural Biology Contributions to the Discovery of Drugs to Treat Chronic Myelogenous Leukaemia","volume":"63","author":"Fendrich","year":"2007","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13321-021-00522-2","article-title":"GNINA 1.0: Molecular Docking with Deep Learning","volume":"13","author":"McNutt","year":"2021","journal-title":"J. Cheminformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/S1359-6446(04)03069-7","article-title":"Ligand Efficiency: A Useful Metric for Lead Selection","volume":"9","author":"Hopkins","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An Advanced Semantic Chemical Editor, Visualization, and Analysis Platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5.6.1","DOI":"10.1002\/0471250953.bi0506s15","article-title":"Comparative Protein Structure Modeling Using Modeller","volume":"15","author":"Eswar","year":"2006","journal-title":"CP Bioinform."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1002\/jcc.21442","article-title":"A Molecular Mechanics Model for Imatinib and Imatinib: Kinase Binding","volume":"31","author":"Aleksandrov","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1021\/jm049546c","article-title":"Acid\u2212Base Profiling of Imatinib (Gleevec) and Its Fragments","volume":"48","author":"Varga","year":"2005","journal-title":"J. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/15\/3101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:15:41Z","timestamp":1760033741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/15\/3101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,24]]},"references-count":29,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["molecules30153101"],"URL":"https:\/\/doi.org\/10.3390\/molecules30153101","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,24]]}}}