Effect of Regiochemistry and Methylation on the Anticancer Activity of a Ferrocene‐Containing Organometallic Nucleoside Analogue

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.

A novel ferronucleoside that targets DNA replication in pancreatic cancer cells

“…In the current study we demonstrate that 1-(S,Rp) is also cytotoxic to a panel of five pancreatic ductal adenoma carcinoma (PDAC) cell lines including one that is resistant to gemcitabine. We have shown previously that non-phosphorylatable analogues of 1-(S,Rp) have similar cytotoxicity to the parent compound (28). Therefore, in contrast to other clinically used nucleobase and nucleoside analogues like 5-fluorouracil and gemcitabine respectively, the mechanism of toxicity of 1-(S,Rp) is independent of substrate phosphorylation and incorporation into genomic DNA.…”

“…We conclude that the mode of action of 1-(S,Rp) is novel and distinct from gemcitabine. Structural activity studies have shown that regiochemistry (28) and length of the hydroxy alkyl linker (21) are key determinants of cytotoxicity. This suggests a specific cellular target rather than a non-specific mechanism of toxicity such as redox cycling of the iron and generation of reactive oxygen species, a mechanism which has been suggested for both the parent ferrocene compound (29,30) as well as other ferrocene analogues including ferrocifens (31,32) and amino ferrocifens (33).…”

Stereo‐Defined Ferrocenyl Glycol Nucleic Acid (Fc‐GNA) Constituents: Synthesis, Electrochemistry, Mechanism of Formation, and Anticancer Activity Studies

“…[37] Fc-XNA has attracted the interest of researchers in recent times. [38][39][40][41] Arguably, the most spectacular achievement in the field of Fc-XNA chemistry was the synthesis of a single-stranded Fc-XNA oligonucleotide containing eight ferrocenyl moieties. [38] Furthermore, it has been shown that the ferrocenyl moiety exhibited superior anticancer activity to the ruthenocenyl moiety when inserted in the otherwise same nucleoside scaffold.…”

“…[39,40] A recent report also highlights the role of regiochemistry and methylation in the cytotoxic activity profile of some Fc-XNA nucleosides. [41] A few years ago, we developed a methodology for the synthesis of Fc-nucleobase adducts. [42] Subsequently, we developed some procedures specific for Fc-XNA nucleosides in which the 1,1'-disubstituted Fc moiety exchanged the D-2'-deoxyribose in canonical nucleosides.…”

Synthesis and biological evaluations of mono‐ and bis‐ferrocene uracil derivatives

“…[20] Furthermore, ferrocene tagged multi-functionalized 1,4-dihydropyrimidines displayed inhibitory activity against human breast cancer cells equal to doxorubicin. [21] The anticancer potential of organometallic nucleoside analogs via the synthesis of ferrocene-nucleobase conjugates was explored [21][22][23][24][25][26][27][28][29][30][31][32] and recently showed that the introduction of a bulky and lipophilic ferrocenylmethylene-ferrocenyl (Fc-CH 2 -Fc) moiety improved the activities compared to that of the single metallocenecontaining compounds. [33] Ferrocenyl alkyl thymine in combined application in vivo with anticancer drug cyclophosphamide demonstrated therapeutic synergism against Lewis lung carcinoma (LLC).…”