Transcript Document

Metallopharmaceuticals as Photoactivatable Anticancer Drugs
Samar Moqadasi1,2, Christine O’Connor1,2, Denis O’Shea2,3 and Michael Devereux2,3.
1School
of Chemical and Pharmaceutical Sciences, Kevin Street, 2Materials Synthesis and Applications (MSA) Research
Group, FOCAS Institute and 3The 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 metallocomplexes 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
(mbpibH2) as shown in scheme 1and the starting materials Ru(L)2CL2 (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.
N
N
N
CHO
NH
NH
N
mfmp
N
mbpibH2
N
N
HN
N
N
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 (mbpibH2)
INTRODUCTION
Historically the first metal based drug for clinical trials was cisplatin, cis-[Pt(NH3)2Cl2] in 1972. 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 tumours6. 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.
RESULTS
70
60
EXPERIMENTAL
O
50
O
40
30
STEP 1
N
LiCl
+
2
N
RuCl3.3H2O
N
N
DMF
8h reflux
Cl
20
phen-dione
N
10
Cl
Ru
N
N
N
3870
1H
Figure 1:
STEP 2
O
a. KBr/H2SO4 +HNO3
3h reflux
b. ice, NaOH
N
3370
2870
2370
1870
1370
870
0
370
Wavenumbers (cm-1)
Synthesis of [Ru(phen)2Cl2]
N
%T
NMR (400 MHz, DMSO-d6 ) 1,10-phenanthroline-5,6-dione
Figure 2: IR 1,10-phenanthroline-5,6-dione
O
N
N
N
N
phen-dione
NH
CHO
D2O Shake
N
Synthesis of 1,10-phenanthroline-5,6-dione
STEP 3
O
O
isophthalic aldehyde
N
CH3COONH4
N
CH3COOH
N
CHO
NH
2h reflux
N
Figure 4: 1H NMR (400 MHz, DMSO-d6 ) mfmp
Exchange with D2O
Figure 3:1H NMR (400 MHz, DMSO-d6 ) mfmp
N
phen-dione
Synthesis of 2-(3-formylphenyl)imidazo[4,5 -f ]-[1,10]phenanthroline (mfmp)
UV/Vis Abs (au)
λ max in MeCN
Complex
[Ru(phen)2mfmp]
STEP 4
O
O
isophthalic aldehyde
N
N
N
N
CHO
NH
N
Ru(phen)2Cl2
4h/Ethanol-water
phen-dione
N
CHO
NH
N
456 nm
Emission
λ max in MeCN
590 nm
Table 1: UV/VIS and Emission Spectroscopy of Ru(phen)2mfmp]
Spectroscopic Characterisation
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 D2O
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)2mfmp] in acetonitrile.
(phen)2Ru
N
CONCLUSION
Synthesis of [Ru(phen)2(mfmp)]
Synthesis of 2-(3-formylphenyl)imidazo[4,5 -f ]-[1,10]phenanthroline (mfmp)
FUTURE STEPS
N
CHO
NH
N
(phen)2Ru
N
phen-dione
NH
N
REFERENCES
H
N
N
N
N
Ru(phen) Cl
2 2
(phen)2Ru
N
N
N
N
NH
N
HN
N
(phen)2Ru
N
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) 2Cl2
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.
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www.chem.ed.ac.uk/teaching/undergrad/chemistry4/lectures/moduleN/MIC/miclecturematerial.pdf
Ru(phen)2
N
Scheme 2: Step-wise synthesis of dinuclear complexes.
ACKNOWLEDGMENTS
Strand 1 R & D funding 2006, Technological Sector Research Initiative NDP 2000-2006.
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..