Effect of regiochemistry and methylation on the anticancer activity of a ferrocene-containing organometallic nucleoside analogue.

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,R p) , which only differs from the lead compound by being substituted on two cyclopentadienyl rings rather than one, was over twenty 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.