Design, Docking Analysis, and Structure-Activity Relationship of Ferrocene-Modified Tyrosine Kinase Inhibitors:...

Area of Science:

• Medicinal Chemistry
• Oncology
• Organometallic Chemistry

Background:

• Ferrocene (Fc) is a redox-active organometallic scaffold with valuable physicochemical and pharmacological properties for drug development.
• Imatinib and nilotinib are established tyrosine kinase inhibitors used in treating BCR-ABL1-positive chronic myeloid leukemia (CML).

Purpose of the Study:

• To synthesize and evaluate novel ferrocene-functionalized analogues of imatinib and nilotinib as potential therapeutics for BCR-ABL1+ CML.
• To investigate the structure-activity relationships and therapeutic potential of these Fc-based derivatives against CML cell lines.

Main Methods:

• Synthesis of four ferrocene-based derivatives (compounds 6, 9, 14, and 18) by substituting pharmacophoric regions of imatinib/nilotinib with ferrocene units.
• Antiproliferative assays against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, LAMA-84) with imatinib as a reference.
• Selectivity assays and molecular docking studies to assess toxicity profiles and binding interactions within the c-Abl kinase ATP-binding site.

Main Results:

• Compounds 6 and 9 showed significant antiproliferative activity against K-562 cells.
• Compounds 14 and 18 demonstrated enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib.
• Compounds 9 and 14 exhibited favorable selectivity towards malignant cells, and molecular docking supported Fc substitution's impact on kinase binding.

Conclusions:

• Ferrocene-functionalized imatinib and nilotinib analogues represent a promising new class of anticancer agents for BCR-ABL1+ CML.
• The observed structure-activity relationships and favorable toxicity profiles warrant further investigation of these compounds as potential CML therapeutics.