Dr Nesrin mwafi

Department of Pharmacology

Faculty of Medicine

Ferrocene Conjugated Nucleosides as Potential Inductors of Apoptosis in Cancer Cells

Nesrin R. Mwafi^{* 1} and  Wjatschesslaw A. Wlassoff ²

¹ Department of Physiology and Pharmacology, Faculty of Medicine, Mu'tah University, Karak 61710, Jordan, E-mail: drnesrin@mutah.edu.jo

² Biomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK E-mail: W.Wlassoff@shu.ac.uk

ABSTRACT

Despite the progress in studying cancer, mortality from the disease has not considerably changed in the last 30 years and treatment of cancer is still a challenge. Therefore, the development of new anticancer drugs is in high demand. Cancerous cells are persistently exposed to more oxidative stress than adjacent normal cells as a result of abnormal regulation of some enzymes. Consequently, excessive amounts of hydrogen peroxide (H₂O₂) are accumulated in tumour cells. Iron-containing compounds, such as ferrocene, can react with H₂O₂  through Fenton reaction where highly reactive hydroxyl radicals are formed. These radicals possess a damaging effect on the DNA of the cancer cells, thereby inducing the apoptosis and inhibiting cancerous cell growth. Ferrocene on its own has no affinity for tumour cells and if administered as it is, it will not be specifically delivered to these targets.

The present study outlines a simple approach for targeting the ferrocene via conjugation with nucleoside. The ferrocene-linked nucleosides are supposed to be preferentially taken up by actively dividing cancerous cells where they are phosphorylated intracellularly into the corresponding nucleotides. These nucleotides will then become incorporated into the cellular DNA. This is advantageous as the radicals will be generated near the DNA, thus making the damage more significant. Basically, the desired compound ferrocene-linked 2’-deoxyuridine was synthesised by two major steps. 2’-deoxyuridine was first mercurated and then alkylated via Heck reaction to form the corresponding C-5 allylamine-linked 2’-deoxyuridine (AA-dU). The ferrocenecarboxylic acid was then linked to AA-dU compound via amide bond formation promoted by coupling reagents such as HBTU and HATU. The synthesised compound was successfully purified to homogeneity by gradient silica gel column chromatography followed by reverse phase C18 HPLC. The structure of the purified product was confirmed by ¹H NMR.

Keywords: DNA, oxidative stress, radicals, apoptosis, ferrocene-linked nucleosides, Heck reaction.

Corresponding author  contact:

Dr. Nesrin R. Mwafi, Department of Physiology and Pharmacology, Faculty of Medicine, Mu'tah University, Karak 61710, P.O.Box (7), Jordan, Tel: 00962799613466.