Title : Ferrocene modified imatinib and niotinib analogues as novel tyrosine kinase inhibitors
Abstract:
Ferrocene (Fc) is an 18-electron organometallic complex composed of a central iron(II) ion sandwiched between two parallel cyclopentadienyl (Cp) ligands. Due to its unique geometry and chemical features, the Fc moiety has been an enticing research subject in organometallic, material and medicinal sciences. Its unusual structure has been exploited for a number of reasons: the high stability in aqueous and aerobic media, the fast and reversible redox change of the extremely stable Fc/Fc+ scaffold that might account for potential selectivity in anticancer activity; the aromaticity and high lipophilicity of the Fc core, which make the structure readily membrane permeable; and most importantly, the non-toxicity and the manifold effects of Fc derivatives on cellular function lend them a special place in medicinal and pharmaceutical chemistry. The unique features of Fc and the need for development of targeted anticancer drugs, inspired the design, synthesis and biological evaluation of ferrocenyl modified tyrosine kinase inhibitors by replacing the pyridyl moiety in imatinib and nilotinib generalized structures with ferrocenyl group, which resulted in compounds, exhibiting anticancer activity comparable or surpassing that of the parent drugs. These results led us to focus our efforts on the synthesis of bigger series of Fc analogues of imatinib and nilotinib. The compounds were evaluated for their anticancer activity in a panel of bcr-abl positive human malignant cell lines using imatinib as a reference drug. The metallocenes exhibited a dose-dependent inhibition on malignant cell growth with a varying antileukemic activity. The most potent analogues were showing comparable or even superior efficacy to the referent. Their cancer selectivity indices suggest a favorable selectivity profile, indicating a 250 times higher preferential activity of 15a towards malignantly transformed K-562 cells and an even twice greater one (500) of 9 in the LAMA-84 leukemic model as compared to normal murine fibroblast cell line.
