Metallopharmaceuticals as Photoactivatable Anticancer Drugs Samar Moqadasi 1,2, Christine O’Connor 1,2, Denis O’Shea 2,3 and Michael Devereux 2,3. 1 School of Chemical and Pharmaceutical Sciences, Kevin Street, 2 Materials Synthesis and Applications (MSA) Research Group, FOCAS Institute and 3 The Inorganic Pharmaceutical and Biomimetic Research Group, Cathal Brugha Street, Dublin Institute of Technology. ABSTRACT Target-based research (treating infected site only), directed towards the design and mechanism of action of metal-based anticancer complexes is expanding rapidly due to the selectivity and activity of such novel therapeutics. The photo activation of Ruthenium (II) complexes as therapeutic drugs has recently escalated as the complexes are suitable for photoactivation due to their well published photochemical and photophysical properties which in turn is the basis of photodynamic approaches to therapy. 1-5 The aim of this study is to synthesise a series of metallo- complexes of which will be tested on tumour and non-tumour cell lines in the Radiation & Environmental Science Centre (RESC) at FOCAS, DIT. The research in this project commenced early this year with the synthesis of 1,10-phen-5,6-dione (phen-dione), 2-(3 -formylphenyl)imidazo[4,5-f]-[1,10] phenanthroline (mfmp) and 1,3-bis([1,10]-phenanthroline-[5,6-d]imidazol-2-yl)benzene (mbpibH 2 ) as shown in scheme 1and the starting materials Ru(L) 2 CL 2 (where L = 2,2’-bipyridyl or 1,10-phenanthroline). Further derivatives of the ligands will be prepared for comparative purposes in the future. Initial therapeutic efficacy of the ligands and their metal complexes shown in scheme 2 will be established first. Scheme 1: Structure of 2-(3-formylphenyl)imidazo[4,5-f]-[1,10] phenanthroline (mfmp) and 1,3-bis([1,10]-phenanthroline-[5,6-d]imidazol-2-yl)benzene (mbpibH 2 ) INTRODUCTION Historically the first metal based drug for clinical trials was cisplatin, cis-[Pt(NH 3 ) 2 Cl 2 ] in It was observed that platinum compounds were causing filamentous growth rather than cell division in Escherichia coli bacterial cells. The idea of their anti-tumour activity. In 1979 cisplatin was approved by the Food and Drug Administration (FDA) as an anti-cancer agent following the success of the clinical trials in human patients. Cisplatin is used to treat testicular, ovarian, bladder, head and neck tumours 6. The toxicity of this drug and its inability to treat many cancer cell lines and metastasis (secondary) cancers presented a challenge for inorganic chemists to develop new platinum based anti-cancer drugs. Some transition metal complexes have attracted considerable attention due to their impressive and useful chemical and physical properties 7. Ruthenium has been selected for this research as Ru (II) polypyridyl complexes have been investigated as photosensitising agents for years and it is hoped to apply this property in photodynamic therapy (PDT). The Ru (II) polypyridyl complex will act as a photosensitiser for possible chemotherapeutic effects. The free ligands will be studied along with the metal complexes to investigate their cytotoxicity. EXPERIMENTAL RESULTS REFERENCES Scheme 2: Step-wise synthesis of dinuclear complexes. Figure 1: 1 H NMR (400 MHz, DMSO-d 6 ) 1,10-phenanthroline-5,6-dione Figure 2: IR 1,10-phenanthroline-5,6-dione Wavenumbers (cm -1 ) %T Synthesis of 1,10-phenanthroline-5,6-dione Synthesis of [Ru(phen) 2 Cl 2 ] Synthesis of 2-(3-formylphenyl)imidazo[4,5 -f ]-[1,10]phenanthroline (mfmp) mfmp mbpibH 2 Figure 3: 1 H NMR (400 MHz, DMSO-d6 ) mfmp Figure 4: 1 H NMR (400 MHz, DMSO-d 6 ) mfmp Exchange with D 2 O CONCLUSION 1. Clarke, M.J., Coord. Chem. Rev., 2002, 232, 1, F. Wang, A. Habtemariam, E.P.L. van der Geer, R. Fernández, M. Melchart, R.J. Deeth, R. Aird, S. Guichard, F.P.A. Fabbiani, P. Lozano-Casal, I.D.H. Oswald, D.I. Jodrell, S. Parsons, P.J. Sadler, Proc. Natl. Acad. Sci. USA, 2005, 102, O. Lentzen, C. Moucheron and A. Mesmaeker, Metallotherapeutic Drugs and Metal-based Diagnostic Agents; The use of Metals in Medicine, Chapter 19, 2005, Wiley and Sons Ltd. 4. Fernandez, R., Melchart, M., van der Geer, E., Wand, F., Habtemariam, A. and Sadler, P.J., J. Inorg. Biochem., 2003, 9, Chen, H., Parkinson, J.A., Morris, R.E. and Sadler, P.J., J. Am. Chem. Soc., 2003, 125, M. Rosette, R. Malone., Bioinorg. Chem: A short Course, 1st Ed., John Wiley and Sons, I nc., P. J. Dyson, S. Gianni, Journal of RSC., 2006, P. Sadler, Ch. Shipman, Metals in Medicine, Accessed by author on April 2007 at: Initial synthesis has commenced involving preparation of the 1,10-phen-5,6-dione (phen-dione), 2-(3-formylphenyl)imidazo[4,5 - f ]-[1,10]phenanthroline (mfmp) and 1,3-bis([1,10]-phenanthroline-[5,6-d]imidazol-2-yl)benzene (mbpibH2) ligands and spectroscopic results suggest that the synthesis has been successful. The complexation of the ligands to Ru(phen) 2 Cl 2 has commenced and further analysis is currently required of these complexes. Current spectroscopic results suggests that the mononuclear complex shows suitable photochemistry for the use as a potential photosensitiser. Future work will be to extend the current synthesis and characterisation in order to commence therapeutic evaluation of the complexes and free ligands. STEP 1 STEP 2 STEP 3 FUTURE STEPS Synthesis of 2-(3-formylphenyl)imidazo[4,5 -f ]-[1,10]phenanthroline (mfmp) Synthesis of [Ru(phen) 2 (mfmp)] Complex UV/Vis Abs (au) λ max in MeCN Emission λ max in MeCN [Ru(phen) 2 mfmp]456 nm590 nm ACKNOWLEDGMENTS Strand 1 R & D funding 2006, Technological Sector Research Initiative NDP Staff of the FOCAS Institute, Dublin Institute of Technology and the School of Chemical and Pharmaceutical Sciences, DIT, Kevin St. The Royal College of Surgeons Ireland.. The NMR in figure 1 suggests that the phendione ligand synthesis was successfully carried out and this is supported by the IR spectrum (in figure 2) of the ligand. In particular at 1692 cm -1 the strong peak refers to the C=O of the phendione. Figure 3 and 4 are NMR spectra of the 2-(3-formylphenyl)imidazo[4,5 -f ]-[1,10]phenanthroline (mfmp) ligand and on D 2 O exchange the NH of the ligand disappears. The presence of the aldehyde group in the mfmp was confirmed by IR spectroscopy. Mass Spectroscopy data will be obtained in the future to confirm the ligand structures. Table 1 shows the maximum wavelength of absorbance and emission of the complex [Ru(phen) 2 mfmp] in acetonitrile. Table 1: UV/VIS and Emission Spectroscopy of Ru(phen) 2 mfmp] STEP 4 D 2 O Shake Spectroscopic Characterisation