Effect of Regiochemistry and Methylation on the Anticancer Activity of a Ferrocene-Containing Organometallic Nucleoside Analogue |
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| Authors: | Media K Ismail Dr Zahra Khan Marium Rana Dr Sarah L Horswell Dr Louise Male Dr Huy V Nguyen Dr Alessio Perotti Dr Isolda Romero-Canelón Edward A Wilkinson Dr Nikolas J Hodges Prof James H R Tucker |
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| Affiliation: | 1. School of Chemistry, University of Birmingham Edgbaston, Birmingham, B15 2TT UK;2. School of Biosciences, University of Birmingham Edgbaston, Birmingham, B15 2TT UK;3. School of Pharmacy, Institute of Clinical Sciences, University of Birmingham Edgbaston, Birmingham, B15 2TT UK |
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| Abstract: | Four new bis-substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure-activity-relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1 -(S,Rp), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1 -(S,Rp), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20 times less cytotoxic. On the other hand, methylated derivatives of 1 -(S,Rp) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1 -(S,Rp) cannot proceed through alcohol phosphorylation and that its geometry and size, rather than any particular functional group, are crucial factors in explaining its high anticancer activity. |
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| Keywords: | Ferrocene anticancer nucleoside analogue bioorganometallic metallodrug |
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