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Effect of Regiochemistry and Methylation on the Anticancer Activity of a Ferrocene‐Containing Organometallic Nucleoside Analogue
Author(s) -
Ismail Media K.,
Khan Zahra,
Rana Marium,
Horswell Sarah L.,
Male Louise,
Nguyen Huy V.,
Perotti Alessio,
RomeroCanelón Isolda,
Wilkinson Edward A.,
Hodges Nikolas J.,
Tucker James H. R.
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000124
Subject(s) - chemistry , ferrocene , regioselectivity , stereochemistry , nucleoside , mtt assay , cyclopentadienyl complex , nucleoside analogue , structural isomer , combinatorial chemistry , methylation , structure–activity relationship , in vitro , organic chemistry , biochemistry , dna , electrode , electrochemistry , catalysis
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 , R p ), 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 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 , R p ) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1 ‐( S , R p ) 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.